Hodgkin's disease: histological classification and diagnosis

J. clin. Path. (1969), 22, 165-182

Hodgkin's disease: histological classificationand diagnosis

R. M. CROSS

From the Royal Air Force Institute ofPathology and Tropical Medicine, Halton, Buckinghamshire

SYNOPSIS A review of the previous histological classifications of Hodgkin's disease seems to showthat they are insufficiently accurate in regard to prognosis and difficult to apply but a detailed studyof a large number of cases suggests that certain criteria allow of subdivision of the disease into types..These criteria are the proportion of mature lymphocytes, the presence of plentiful maturehistiocytes, the presence of fibrous nodularity, and the numbers of abnormal reticulum cells andtheir degree of anaplasia.

Three primary histological subdivisions seem to arise from a study of 302 patients, namely, thereticular, histiocytic, and nodular sclerosis groups. These are further divided into well differentiatedand poorly differentiated on the basis of their lymphocyte content and the degree of anaplasia of theabnormal reticulum cells.The histological appearances of each type are described. The application of this histological

classification has been shown to correlate well with the clinical outcome.

In 1832, Thomas Hodgkin described seven patientswho had a disease characterized by generalizedlymphadenopathy and splenomegaly, to which, in1865, Wilks gave the name Hodgkin's disease. Theaetiology of the disease is as obscure today as itwas then.The terminology associated with Hodgkin's

disease is confusing. Greenfield (1878) used thenames lymphadenoma and Hodgkin's diseasesynonymously; the term Hodgkin's 'granuloma'probably arose from Stemnberg's (1898) work.Letterer (1924) introduced the term reticulosis todescribe any progressive hyperplasia of the reticulo-endothelial system; on this basis, Pullinger (1932)referred to Hodgkin's disease as fibromyeloidreticulosis, and Robb-Smith (1938) divided his casesof Hodgkin's disease into lymphoreticular andfibromyeloid forms of medullary reticulosis. Galland Mallory (1942) introduced a classification ofmalignant lymphoma in which Hodgkin's diseasewas divided into Hodgkin's lymphoma andHodgkin's sarcoma.

CLASSIFICATION OF JACKSON AND PARKER (1944)

A major step in classification was the work ofJackson and Parker (1944), who divided Hodgkin'sdisease into early Hodgkin's disease (later calledReceived for publication 24 July 1968.

paragranuloma), granuloma, and . sarcoma. Thisclassification has been used for many years and theproportion of these three types of Hodgkin's diseaseas reported in the literature, is seen in Table I.Paragranuloma has long been recognized as havinga favourable prognosis and Hodgkin's sarcoma apoor one. These two groups, however, representedless than 20% of the total number of cases ofHodgkin's disease.

TABLE ICLASSIFICATION OF HODGKIN'S DISEASE INTO THREE TYPESBY JACKSON AND PARKER AND DISTRIBUTION OF CASES IN

OTHER SERIESAuthor Classification

Jackson and Parker (1944)

Smetana and Cohen (1956)

Wright (1956)

Hilton and Sutton (1962)

Hanson (1964)

Lukes (1963)

65

ParagranulomaGranulomaSarcomaParagranulomaGranulomaSarcomaParagranulomaGranulomaSarcomaParagranulomaGranulomaSarcomaParagranulomaGranulomaSarcomaParagranulomaGranulomaSarcoma

No.of Cases

28 (10%)136 (79%)32 (11 %)35 (10%)

308 (89%)5 (1%)

19 (7%)157 (90%)10 (3%)12 (5%)

137 (94%)3 (1%)

22 (12%)154 (84%)

8 (4%)30 (8%)

344 (91%)3 (I O)

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The main disadvantage of the classification ofJackson and Parker was that on average 80% of thecases fell into the 'granuloma' group, and had suchvaried survival times that there was little prognosticvalue in the classification. Because of the limitationin the Jackson and Parker classification, thereappeared to be some justification for the opinions ofPeters (1950) and Aisenberg (1964) that clinical'staging' of Hodgkin's disease on first presentationof the illness was a more reliable guide to prognosisthan histology.

CLASSIFICATION OF LUKES AND BUTLER (1966)

Lukes (1963) and Lukes and Butler (1966)proposed a classification based on the predominanthistological features: (1) lymphocytic and/or histio-cytic nodular; (2) lymphocytic and/or histiocyticdiffuse; (3) nodular sclerosis; (4) mixed; (5) diffusefibrosis; and (6) reticular. They claimed that therewas a 'definite relationship between the histologicalfindings, clinical stages, and survival'.They emphasized that 'numerous terms have been

proposed for the lesion with a predominance oflymphocytes but none clearly reflected the histologiccharacter or the almost constant association withhistiocytes which at times may overshadow thelymphocytic component'. There is some doubt as towhat Lukes and Butler mean by the term 'histiocytes'and this is discussed below.Using the terms lymphocytic and/or histiocytic,

diffuse or nodular, Lukes andButler (1966) recognizedfour histological types originating from two of thetypes of Jackson and Parker (1944).

1 Cases which would have been called 'para-granuloma' by Jackson and Parker (1944): theseshowed a predominantly lymphocytic proliferationwith few histiocytes and were divided into nodular ordiffuse.

2 Cases which would have been called 'granuloma'by Jackson and Parker (1944) and showed a pre-dominance of histiocytes, divided into nodular anddiffuse.

Thirty-three out of 66 lymphocytic and histiocyticcases in the series of Lukes and Butler (1966)showed histiocytic predominance. The survival timein the lymphocytic and histiocytic cases was long butfailed to show such a significant difference inprognosis as to justify separation of the cases intonodular or diffuse.The third and fourth group of Lukes and Butler,

ie, nodular sclerosis and mixed cellularity, are sub-divisions of the 'granuloma' group of Jackson andParker (1944). In their series, Lukes and Butler (1966)considered that 40% of all their patients with

Hodgkin's disease were of the nodular sclerosis type,a figure which has not been approached in any ofthe other series; the highest incidence was 150%(Hanson, 1964; Harrison, 1966; Cross, 1968). Thereason for this discrepancy would appear to stemfrom the fact that Lukes and Butler (1966) basedtheir subdivision largely on the amount and patternof fibrous tissue; they placed great emphasis on thebirefringent character of the collagenous fibroustissue. The presence of birefringence, in my opinion,merely reflects how long the fibrous tissue has beenpresent in the lymph gland. Nodular sclerosis wasconsidered by Lukes and Butler (1966) to be a lesionof major prognostic significance in stage I cases(Peters and Middlemiss, 1958), but, in their series,only a third of the cases of nodular sclerosis couldbe considered as having a good prognosis.The description of the 'mixed' group (4) is rather

vague. It appears to represent the 'granuloma' typeof Jackson and Parker (1944), with the followingcases removed: those which have fibrosis arrangedin a nodular pattern and show birefringence, ie,nodular sclerosis; those in which normal reticulumcells predominate (histiocytes), ie, lymphocytic and/or histiocytic diffuse; those which show advanced,ie, diffuse, fibrosis; and those composed 'pre-dominantly of Sternberg Reed cells where pleo-morphism is absent'. When all these types areremoved from the 'granuloma' group, there is verylittle remaining on which the diagnosis of a 'mixed'group can be based.The fifth group 'diffuse fibrosis', referred to in the

American nomenclature as the 'fibrillary' type ofHodgkin's disease, is described by Lukes and Butler(1966) as generally composed of 'compact, hypo-cellular amorphous proteinaceous material thatresembles precollagen'. It is not clear why this iscalled 'fibrosis'.

RYE CLASSIFICATION: CLASSIFICATION OFLUKES AND BUTLER (1966) MODIFIED

At the conference on Hodgkin's disease in Rye,New York, in September 1965, a nomenclaturecommittee, with R. J. Lukes as chairman, deliberatedon the most suitable terminology for the histologicalclassification of Hodgkin's disease and the followingclassification, based on the 'histologic expressions ofHodgkin's disease described by Lukes and Butler atthe conference', later published (1966), was adopted:lymphocytic predominance, nodular sclerosis, mixedcellularity, and lymphocytic depletion.

Lymphocytic predominance included the para-granuloma type of Jackson and Parker (1944) andalso the lymphocytic and/or histiocytic types, bothnodular and diffuse, of Lukes and Butler (1966).

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Hodgkin's disease: histological classification and diagnosis

Lymphocytic depletion included the diffuse fibrosisand reticular types of Lukes and Butler (1966) andthe sarcoma type of Jackson and Parker (1944).Selection of the term 'Iymphocytic predominance',based on the inclusion of the group lymphocytic and/or histiocytic, nodular or diffuse of Lukes and Butler(1966), can be confusing. In more than 50% of theirlymphocytic and histiocytic cases histiocytes were'predominant'. There is an apparent contradictionin nomenclature since a case can hardly be includedboth under the heading of lymphocytic predomi-nance and histiocytic predominance.The general principle of distinguishing cases

showing lymphocytic predominance or lymphocyticdepletion is no doubt excellent, but, in my opinion,histologists may tend to equate lymphocyticpredominance with paragranuloma and lymphocyticdepletion with sarcoma. The value of the classifica-tion appears to me to lie in the division of granulomainto nodular sclerosis and mixed cellularity; asindicated above, it is not always easy to make ahistological differentiation between these two groupson the criteria given by Lukes and Butler (1966) noris there good enough correlation with prognosis.The classification adopted at Rye thus appears to

lack histological precision and fails to fulfil the needfor a universally acceptable histological classificationwhich will give a reliable guide to the likely courseof the illness.

TERMINOLOGY

The Rye classification also raised the importantproblem of cell nomenclature. Lukes and Butler(1966) refer to 'the lymphocytic proliferation inHodgkin's disease usually in association with vary-ing numbers of reactive histiocytes'. The term'histiocytic lymphoma' is used synonymously with'reticulum cell sarcoma', when they claim supportfor the neoplastic nature of Hodgkin's disease andthey say that the 'reticulum cell proliferation inHodgkin's disease involves not only the abnormalreticulum cell of the Stemnberg Reed type, but also areactive histiocyte that is possibly related to the for-mation of fibrillar reticulum, the fibroblastic com-ponent and eventually fibrous connective tissue'. Intheir description of the 'variation in the histologicalfindings', they refer to 'the variety of reticulumcells in Hodgkin's disease: these include (a) theabnormal reticulum cells or the Sternberg Reedcells; (b) the peculiar polypoid reticulum cells foundin lymphocytic and histiocytic types; and (c) reactivereticulum cells or histiocytes which have abundantpale eosinophilic cytoplasm and large vesicular nucleiwithout prominent nucleoli. They do not mentionthe presence of normal reticulum cells.

It is impossible to discuss in detail in this paper

the controversy on the nomenclature of 'reticularcells' but Marshall (1956) stated that Maximow(1932), who was one of the greatest authorities onthis work, considered that there were two distincttypes of cells associated with the reticulin fibres oflymphatic tissue, one a phagocytic cell and the othera non-phagocytic cell able to produce all the othercell types of the reticular tissue. Gall and Mallory(1942) accepted the idea of these two cells when theyused the terms 'clasmatocyte' (and its synonymsmacrophage cell and histiocyte) and stem cell (andits synonym, reticulum cell). In their description ofHodgkin's lymphoma, which was considered to bepolycellular, the cell components were made up ofgranulocytes, lymphocytes, plasma cells, clasmato-cytes, and fibroblasts, all cells found in inflammatoryconditions, but in addition the feature essential toHodgkin's disease was the presence of stem cellswhich tended strongly to develop large multilobedor multinucleated forms. The presence of normalstem cells or reticulum cells was not mentioned. Theterm 'reticulum cell' has been used by some authors(Jackson and Parker, 1947) synonymously with thehistiocyte or clasmatocyte.As will be shown, I prefer to use the terms usually

made acceptable in Britain and distinguish betweenhistiocytes which occur in a wide variety of con-ditions such as sarcoidosis or toxoplasmosis as wellas in Hodgkin's disease, and reticulum cells whichare a feature of normal and reactive inflammatorylymph nodes. When Lukes and Butler stated that inHodgkin's disease the lymphocytic proliferation wasusually associated with histiocytes of reactivecharacter, it is possible that they meant normalreticulum cells. The confusion in terminology isevident in a recent paper by Franssila, Kalima, andVoutilainen (1967); they used the classification ofLukes and Butler and described reactive histiocyticcells in such a way as to show that they referred tocells which pathologists in Britain would call 'normalreticulum cells'.

In a review of 302 patients with Hodgkin's diseaseat the histopathology centre of the Royal Air ForceInstitute of Pathology and Tropical Medicine,Halton, who presented between 1940 and 1967, aclassification of Hodgkin's disease was evolved. Itis believed that this is an improvement upon previousclassifications and it is particularly valuable in thatit provides a better basis for prognosis.

Before describing in detail the specific histologicalfindings used in the diagnosis of Hodgkin's diseaseand its subsequent classification, it is necessary todefine, for the purpose of classification, the celltypes seen in formalin-fixed, haematoxylin-and-eosin-stained paraffin sections of normal lymphglands and glands from Hodgkin's disease.

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THE CYTOLOGY OF NORMAL LYMPH GLANDS AND

GLANDS FROM HODGKIN'S DISEASE

SIZE OF CELLS The size of the cell is generallydescribed as the diameter of the area of cytoplasm.However, in a large number of the cells, it isimpossible to delineate the extent of the cytoplasmand in all cell measurements it is proposed to includeonly the size of the nucleus.Normal reticulum cells With a nucleus 10 to

12 ,^ in size (Fig. 1), they are stellate in appearance;the nuclear membrane is well defined, the chromatinarranged in small, fine particles and there may beone, two, or three small darkly stained nucleoli.

Histiocytes These are 10 to 15 ,u in size (Fig. 2),the cell outlines are distinct, and there is abundantpale, often staining pink, slightly granular cytoplasm.The oval or kidney-shaped nucleus is usually situatedat one pole of the cell, leaving a considerable amountof cytoplasm evident. The chromatin particles are

fine and distributed evenly throughout the nucleus.The nucleolus is small and darkly stained.Abnormal reticulum cells (Sternberg Reed cell)

The abnormal reticulum cell (Figs. 3, 5, and 7) or

Sternberg Reed cell is generally regarded as theessential prerequisite for the diagnosis of Hodgkin'sdisease: lymphocytes, plasma cells, eosinophils, andpolymorphs indicate a reactive process but theirpresence is valuable in establishing the diagnosis.The abnormal reticulum cells were originally

described by Sternberg (1898) and Reed (1902), butthe latter author's description of giant cells, whichshe claimed, were 'peculiar' to Hodgkin's disease,could fit numerous cells seen in other diseases of thereticuloendothelial system.The form of abnormal reticulum cell which most

histologists regard as pathognomonic of Hodgkin'sdisease is the binucleate (Fig. 6) 'mirror image' cell(Pullinger, 1932). It is significant to find these cellsin a gland when Hodgkin's disease is suspected, butthey may be extremely difficult to find and thediagnosis could be missed.The varying opinions as to what constitutes a

Stemnberg Reed cell account for many of thediagnostic errors; Karnofsky (1966) estimated thatthe diagnosis of Hodgkin's disease was wronglymade in at least 20o% of cases.

There has been a tendency by some authors(Dawson and Harrison, 1961; Hanson, 1964) toaccept the definition of the Stemnberg Reed cellgiven by Smetana and Cohen (1956) and an overallminimum cell diameter of 15 ,u was accepted. Theexact definition, however, is not completely clear.Smetana and Cohen indicated that the nuclearmembrane had many outcroppings and folds thatoften caused the cell to appear multinucleated.

Later they also indicated that the cells with single,not folded, nuclei and amphoteric nucleoli were notdiagnostic of Hodgkin's disease. Dawson andHarrison, however, described Steinberg Reed cellswith single round nuclei and also cells with two ormore discrete nuclei.Lukes and Butler (1966) also emphasized the

variation in the cytological features of SternbergReed cells, but they regarded only cells withcharacteristic 'multinucleated, binucleated and lob-ated forms with huge inclusion-like nucleoli' asreliable and essential for the diagnosis of Hodgkin'sdisease, and they considered that the mononuclearforms with similar nuclear and cytoplasmic appear-ance could be found in lymphoid reactions of viralinfections.The criteria of Smetana and Cohen (1956) and

Lukes and Butler (1966) are considered to be toorestrictive and a more acceptable description of theSternberg Reed cells is proposed as follows. Thesize varies from 15 to 60 ,u. The nucleus is enlargedin relation to the amount of cytoplasm. Uptake ofthe haematoxylin stain varies. The size of the nucleusvaries and there is pronounced infolding. Thechromatin is irregularly distributed. It may have atrabecular arrangement, or appear as small denseclumps with indefinite outlines, particularly aroundthe nuclear membrane which is thickened. Chromatinis scanty around the nucleolus, producing a haloeffect. The nucleolus is large, irregularly shaped, andusually stains eosinophilic. Abnormal mitosis ispresent in the Sternberg Reed cells. Necrobiosisis a feature in some of the Sternberg Reed cells.The tendency for Sternberg Reed cells to undergo

necrobiosis (Fig. 16) in Hodgkin's disease wasemphasized by Jackson and Parker (1944). Littleattention has been given to these cells by subsequentauthors. They are degenerating and pyknotic cells,the cytoplasm is indefinite, and the nucleus, withlittle chromatin pattern, is pleomorphic, stainsheavily with the haematoxylin stain, and is easilydistinguishable from the other cells in the lymphgland. Although not pathognomonic, the diagnosisof Hodgkin's disease can seldom be made in theirabsence.

PRESENT SERIES

The present study is based on 302 cases of ma-lignant lymphoma occurring in Royal Air Forcepatients from 1940 to 1967. Attention was directedto the correlation between the histological findingsin the lymph gland and the survival time of thepatient. Many criteria were studied and it was foundthat certain ones enable Hodgkin's disease to besubdivided on morphological grounds. Normal and

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abnormal reticulum cells were present in varyingnumbers and transitions were observed fairlyreadily as described by Dawson and Harrison (1961).The criteria were the proportion of mature lympho-cytes (Fig. 3); the presence of plentiful maturehistiocytes (Fig. 9); the presence of a pronouncednodular fibrous tissue pattern (Fig. 14); and theproportion of abnormal reticulum cells and theirdegree of anaplasia (Figs. 4, 6, 7, and 8). Othercriteria, such as the presence of eosinophils, plasmacells, and polymorphonuclear leucocytes, were

investigated but were found to lack significantprognostic importance.

HISTOLOGICAL CLASSIFICATION

On histological grounds, therefore, it was possibleto divide patients with Hodgkin's disease into threegroups.

1 RETICULAR GROUP Composed essentially of thenormal reactive cells and abnormal reticulum cells,but with no significant number of histiocytes and no

definite nodular fibrous pattern.

2 HISTIOCYTIC GROUP In addition to the normalreactive cells and abnormal reticulum cells, therewere large numbers of histiocytes.

3 NODULAR SCLEROSIS GROUP The significant find-ings were the formation of a nodular fibrous pattern,which consisted of collagenous fibrous bandsencircling lymphoid tissue, amongst which were

characteristic large abnormal reticulum cells withabundant clear cytoplasm and irregularly shapedmultilobed nuclei.By assessing the relative numbers of lymphocytes

and abnormal reticulum cells in the lymph gland andthe degree of anaplasia of the abnormal reticulumcells, each group was divided into well differentiatedand poorly differentiated. In the reticular group itwas feasible to divide into three types, lymphocytic,well differentiated, and poorly differentiated.

RETICULAR GROUP

LYMPHOCYTIC TYPE (PARAGRANULOMA OR BENIGN

HODGKIN'S DISEASE) Twenty-six (9 %) patients (Figs.3 and 4) were thus classified.The use of the term 'paragranuloma' to indicate

a lesion with a preponderance of lymphocytes isconsidered to be unsatisfactory, as Hodgkin'sdisease is no longer thought to be a granulomatouscondition. Benign Hodgkin's disease is also unsat-isfactory as this type of Hodgkin's disease is a lethalcondition. Therefore the term reticular lymphocytic

type, indicating those cases in which there are largenumbers of normal lymphocytes and few abnormalreticulum cells, was selected as being moreappropriate.

Follicular pattern In 21 of 26 glands the normalfollicular pattern was completely obliterated, in fivethere was partial loss. The capsule was thickened infive glands, but not in 21. A lobular pattern waspresent in 18; eight showed a diffuse pattern. Thelobular pattern, when present, was poorly definedand the tissue was divided into rounded masses byreticulin bands, best demonstrated by reticulinstains; the degree of fibrosis and the cellular com-position of the lobule did not resemble the appear-ances seen in either nodular sclerosis or giantfollicular lymphoma.Lymphocytes There was an even proliferation of

mature lymphocytes throughout the gland; theyappeared to be normal on routine histologicalexamination. Lymphocytes formed from 75 to95% of the cell population of the gland; no mitoticfigures were seen.

Reticulum cells Normal reticulum cells, moder-ately numerous, were easily identified throughout thegland, but the characteristic feature was the presenceof abnormal reticulum cells, which varied in sizefrom 12 to 25 ,u. They were found diffusely spreadthroughout the gland, and never in clusters. Themajority of the cells had a single nucleus, some werebinucleate, and an occasional cell had three nuclei.The nuclear membrane was markedly infolded; thechromatin pattern was delicate and the nucleolususually small. Necrobiotic cells, though scanty, wereeasily identified.

Other cells Normal histiocytes and fibroblastswere scanty; a small number of plasma cells werefrequently present, but eosinophils and polymorphswere absent.

WELL DIFFERENTIATED TYPE Seventy-seven (25 %)patients (Figs. 5 and 6) were of this type.

Follicular pattern The normal follicular patternwas completely obliterated in 62 of 78 glands; in16 there was partial destruction. The amount offibrosis was variable. In 27 glands there was nothickening of the capsule and general fibrosis wasminimal; in 51 glands there was marked thickeningof the capsule, and in 12 glands there were irregularareas or bundles of fibrous tissue throughout thewhole or part of the gland. Although some of thefibrous tissue was birefringent, it did not form thedistinctive pattern seen in nodular sclerosis. Necrosiswas present in three cases.Lymphocytes The normal mature lymphocyte

was the predominant cell type forming between50 and 75 % of the cell population.

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FIGi. 2.

FIG. 1. Normal lynmph gland.Normal reticulum cell (arrowv)with vesicular nucleus andsmall nucleolus. Cytoplasmill-defined. H & E x 400.

FIG. 2. Reactive lymph nodeshowing epithelioid histiocyteswith oval nucleus (arrow), smallnucleoli, and bulky cytoplasm.H & E x 200.

FIG. 3. Reticular group:lymphocytic type (para-granuloma) showingpredominance of lymphocytesand a central abnormalreticulum cell (arrow). A fewnormal reticulum cells are alsovisible. H & E x 400.

FIG. 3

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FIG. 6.

_t5jjb<ft FIG. 4. Reticular group:4t*~ lymphocytic type (paragran-

uloma) showing a rathersmall abnormal reticulum cell(nucleus 20 ,t diameter).H & E x 900.

FIG. 5. Reticular group: welldifferentiated type. Lym-phocytes still predominantbut abnormal reticulum cellsmore numerous and larger.H & E x 400.

FIG. 6. Reticular group:well differentiated type. Bi-nucleate abnormal reticulumcell (Sternberg Reed) withlarge nucleoli andperinucleolar

Am . ^ L halo.H&E x 900.

FIG. 4.

FIG. 5.

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FIG. 7.

FIG. 7. Reticular group:poorly differentiated type.Lymphocytic depletion,

A. abnormal reticulum cells pre-dominate, wide variation of* .^ :Bb> .., _, W l _:' fi ' .ficell size and morphology._H&E x 400.

FIG. 8. Reticular group:poorly differentiated type.Grossly abnormal reticulum

4 ~~~~~~~~~~~~~~~~cell.The nucleus is hyper-chromatic, multilobed, andshows bizarre configurations.H & E x 900.

FIG. 8.

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FIG. 9. Histiocytic group: well differentiated type. Most of this field is composed oflymphocytes andepithelioid histiocytes. H & E x 100.

FIG. 10. Histiocytic group:well differentiated type. Thisshows lymphocytes, epithelioidhistiocytes, and a cluster ofabnormal reticulum cells onwhich the diagnosis ofHodgkin's disease isconfirmed. H & E x 400.

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FIG. 1L. FIG. 13.FIG. 11. Histiocytic group: well differentiated type showing epithelioid histiocytes with a Langhans' type giant cell.Abnormal reticulum cells not seen in this field. H & E x 400.

FIG. 13. Histiocytic group: poorly differentiated type. A large abnormal reticulum cell with peripheral nuclei andprominent nucleoli superficially resembling a Langhans' giant cell. The rest of the field shows histiocytes and lymphocytes.H & E x 400.

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FIG. 12. Histiocytic group:poorly differentiated type.Lymphocytes and abnormalreticulum cells form most ofthis field but groups of smallpale epithelioid histiocytes arestill visible. H & E x 100.

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FIG. 14. Nodular sclerosisgroup: well differentiatedtype. Dense collagen dividesup lymph node into nodulescontaining lymphocytes andpaler abnormal reticulumcells. One large lacuna cell isseen. H& E x 25.

FIG. 15. Nodularsclerosis group:well differentiated

t type. Higher magni-a7' fication ofpart of

Figure 14..~H&E x 100.

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A44*. t i i i FIG. 16. Nodular sclerosis group: welldifferentiated type. One necrobiotic cell is seen.This cell is seen in all types of Hodgkin's disease.H & E x 400.

FIG. 17. Nodular sclerosis group: poorlyV l Lt=differentiated type. The nodular pattern is similar

to that in Figure 14, but lymphocytes no longerpredominate. H & E x 25.

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Reticulum cells Normal reticulum cells could berecognized, but the abnormal cells outnumberedthem, and in contrast to the lymphocytic type, theywere arranged in irregular collections throughoutthe gland. Pleomorphism and hyperchromasia wereprominent features, and although there were anumber of cells with a single nucleus, the proportionof binucleated cells was greater than in the lympho-cytic type. In addition, the infolding of the nucleuswas more pronounced, the chromatin pattern wascoarser and arranged in irregular clumps: the halosurrounding the nucleolus was more pronouncedthan in the reticular lymphocytic type: the nucleoluswas large, round, or sausage shaped, often stainingbright red. Necrobiotic cells were a prominentfeature; they varied considerably in size and pattern,and were easily recognized. In the abnormalreticulum cells mitotic figures were present invarying numbers.

Other cells Eosinophils and plasma cells werealways present in varying numbers, diffusely spreadthroughout the gland, or collected in groups.

POORLY DIFFERENTIATED TYPE Ninety-seven (35 %)patients (Figs. 7 and 8) were thus classified.

FIG. 18. Nodular sclerosisgroup: poorly differentiatedtype. Higher magnificationof Figure 17, to show thepredominance ofabnormalreticulum cells. H & E x 100.

The exact definition of the type called Hodgkin'ssarcoma by Jackson and Parker (1944) has alwayscaused some difficulty. The incidence recorded byvarious authors, as shown in Table I, varied from1 to 10%. Other authors (Lumb and Newton,1957; Symmers, 1958) considered it impossible toseparate Hodgkin's sarcoma from reticulum cellsarcoma. Hilton and Sutton (1962) observed howrarely the diagnosis of Hodgkin's sarcoma (1 %) wasmade in their series, and they considered that so-called Hodgkin's sarcoma was better regarded asreticulum cell sarcoma. In the proposed classificationthe term 'sarcoma' has been avoided; as a result ofthe emphasis placed upon the abnormal reticulumcells, cases, which previously would have beencalled sarcoma, are included in the poorly differ-entiated types of the various groups.

Follicular pattern In 96 of 99 glands the normalfollicular pattern was completely obliterated. In 30the capsule was thickened and invaded by abnormalreticulum cells, which were often seen in the peri-nodal tissue. In 27 a variable amount of fibroustissue was present, arranged in irregular bundles.Areas of necrosis were present in 48 glands.Lymphocytes Less than 50% of the cell popula-

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R. M. Cross

tion were normal lymphocytes, and they were oftenfound in small groups.

Reticulum cells Normal reticulum cells wererarely found, and abnormal reticulum cells com-prised 50 to 80% of the total cells. Pleomorphismand hyperchromasia were pronounced. Multi-nucleated cells were prominent, and typical bi-nucleate cells were easily found, but a highproportion of the cells had a single nucleus. Thechromatin pattern in most of the cells was coarse andirregularly dispersed throughout the nucleus. Thenucleolus was large, mainly round, and appearedbright red. Abnormal mitotic figures were numerous.The presence of large numbers of necrobiotic cellswas a special feature.

Other cells Plasma cells and eosinophils wereprominent, and numbers of polymorphs wereassociated with necrotic areas.

ANAPLASIA IN THE ABNORMAL RETICULUM CELLSApart from the proportions of the different celltypes used to divide cases into well and poorlydifferentiated there was also a difference in thedegree of anaplasia of the abnormal reticulum cellsin the three types; those in the lymphocytic reticularwere less anaplastic than those in the well differ-entiated reticular type, and those in the poorlydifferentiated reticular type showed the mostanaplastic features of all. A summary of the criteriaused is seen in Table II.Lymphocytic reticular type The majority of the

abnormal reticulum cells were single (Fig. 4), butbinucleated and multinucleated cells were occasion-ally seen in which all the lobes had similar

characteristics. The nuclear membrane was thin witha few dots upon it. The chromatin pattern wasdelicate and lightly stained. The nucleolus wasgenerally small and stained weakly eosinophilic.

Well differentiated type Although the majorityof the abnormal cells had single nuclei the number ofbinucleated and multinucleated (Fig. 6) cells wasgreater than in the lymphocytic type. The nuclearmembrane was thickened and the chromatin patternwas coarse and arranged in irregular collections.There was a characteristic lack of chromatin roundthe nucleolus which produced a 'halo' effect. Thenucleolus was invariably four times the normal size,and stained bright red with haematoxylin and eosin.Poorly differentiated reticular type The out-

standing feature was the degree of pleomorphismand hyperchromatism with large numbers of multi-nucleated cells (Fig. 8). In the more primitive types,however, the majority of the cells had a singlenucleus and binucleated cells were sometimesdifficult to identify.The nuclear membrane was thickened and the

chromatin arranged in dense clumps, againproducing a 'halo' effect around the large nucleolus.Although there was marked infolding of the nucleus,distinct lobules were rarely seen, and the nucleuspresented large irregular amoeboid projections,producing bizarre configurations. Abnormal mitoticfigures were plentiful.

HISTIOCYTIC GROUP

In addition to the abnormal reticulum cells, thefindings which placed a lymph gland in the histiocytic

TABLE IISUMMARY OF CRITERIA USED TO SEPARATE THE RETICULAR GROUP INTO THREE TYPES

Pattern Lymphocytes Other Cells

Fine lobular pattern,little fibrosis, nonecrosis

Coarser patternwith fibrosis moreprominent, occasionalnecrosis

Poorly differentiated Coarse pattern withfibrosis, necrosisinvariably present

More than 75% of thecell population

50 to 75% of the cellpopulation

Less than 50% of thecell population

Normal reticulum cells,fibroblasts, and plasmacells present in smallnumbers; eosinophilsextremely scanty

Moderate numbers ofnormal reticulum cells;large numbers ofeosinophils and plasmacells; few polymorphs

Few normal reticulumcells; large numbers ofeosinophils and plasmacells; large numbers ofpolymorphs

Little pleomorphism; less than 10%of cell population, arrangeddiffusely; single cells common andbinucleated cells difficult to find;chromatin pattern fine and evenlydistributed; nucleolus small, oftenabsentModerate pleomorphism; average10 to 40% of cell population;arranged in clusters, moderatenumbers of binucleated andmultinuceated cells present;chromatin pattern coarse anddistributed in clumps; nucleoluslarge, eosinophilic and invariablypresentMarked pleomorphism; more than40% of cell population arranged insheets and clusters; many singlenuclear cells; binucleated andmultinucleated cells found in largenumbers; chromatin pattern coarseand arranged in clumps; largeeosinophilic nucleolus present

Type

Lymphocytic

Well differentiated

Abnormal Reticulum Cells

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group are: 1 The presence of significant numbers ofnormal histiocytes spread diffusely throughout thegland, especially close to the peripheral sinus, orarranged in multiple foci closely simulating theappearance seen in Boeck's sarcoidosis or toxo-plasmosis. Small numbers of typical Langhans' typecells were often present (Fig. 11). Caseation necrosiswas not found, and all attempts to demonstratetubercle bacilli have proved negative. 2 Pathogno-monic abnormal reticulum cells, which were alwaysmultilobed, measuring 20 to 40 ,t in size, werepresent. Some of them had the nuclei arranged in ahaphazard manner throughout the cell, while othersappeared to have the nuclei arranged in a horse-shoepattern. In both types, however, the nuclei showedinfolding of the membrane, the chromatin patternwas irregular, and the nucleolus was often prom-inent (Fig. 13).

PATTERN Apart from the generalized increase ofdensity of the reticulin there was no specific patternsuch as lobular formation.

RETICULUM CELLS All the cells, as describedin the reticular group, were found.

OTHER CELLS Plasma cells and eosinophils wereprominent in all cases.On the basis of the criteria used to subdivide the

reticular group, ie, more or less than 50% of the totalcell population as normal lymphocytes, the propor-tion of abnormal reticulum cells and the degree ofanaplasia, the patients in the histiocytic group wereclassified as of the well differentiated type (7 %) andthe pathology is seen in Figs. 9, 10, and 11, andof the poorly differentiated type (5%) as seen inFigures 12 and 13.

NODULAR SCLEROSIS GROUP

Two findings which placed a lymph gland in thenodular sclerosis group were (1) the presence ofnumbers of fibroblasts producing excessive amountsof collagenous fibrous tissue typically arranged in anencircling manner, and (2) the presence of character-istic large abnormal reticulum cells.

FIBROUS PATTERN A various amount of fibroustissue was present in the lymph glands of patientswith nodular sclerosis, showing separation intoirregularly shaped, mostly round, nodules ofabnormal lymphoid tissue, surrounded by inter-connecting bands of dense fibrous tissue. Thenodules varied in size from 025 to 3 mm. Insome of the glands there were irregular sheets offibrous tissue in addition to the encircling bands.

In two patients fibrosis in the glands was moderate,

appearing as fine strands running throughout, sothat a nodular appearance was not obvious. How-ever, in both cases, abnormal reticulum cells,typically seen in nodular sclerosis, were present, andsubsequent biopsies, taken during the course of theillness, showed definite nodular patterns.

ABNORMAL RETICULUM CELLS In addition to thevaried pattern of abnormal reticulum cells, asdescribed in the reticular group, the followingcharacteristic cells were present. These ranged from40 to 50 u in size, with abundant pale-stainingcytoplasm. They appeared to produce a spacebetween the cell and the rest of the tissue, andconsequently were called 'lacuna' cells by Lukes andButler (1966) and are shown in Figure 14. Markedinfolding of the nucleus was present, giving rise to avarying number of lobules. The nuclear membranewas thin and sharply defined. The chromatin wasdelicate, and the nucleolus tended to be small andinconspicuous.

OTHER CELLS Eosinophils and plasma cells were aconstant feature of the glands, arranged diffusely, orin clumps. In addition, a small number of normalhistiocytes were often present. In some cases therewere small islands of necrosis, considered to beavascular in origin, and polymorphs were present inthe surrounding areas.By estimating the relative proportion of normal

lymphocytes, and abnormal reticulum cells, and thedegree of anaplasia of the latter cells, the cases werefurther subdivided into the well differentiated type(34 cases, 13 %) as illustrated in Figures 14, 15, and16. The nodular pattern, as described, was pro-nounced, but the degree of fibrosis throughout wasincreased. In general, the cellular composition of thenodule was predominantly lymphocytic and abnor-mal reticulum cells were scanty. The poorly differ-entiated type was seen in 12 (4 %) cases (Figs. 17 and18). The nodular pattern was apparent, but thenodules were not as clear cut as in the well differ-entiated type. Some appeared to be coalescing. Bothwithin and outside the nodules, the number oflymphocytes was considerably reduced. Abnormalreticulum cells were predominant and occasional'lacuna' cells could be identified. An outstandingfeature was the presence of necrosis, sometimesexcessive. Surrounding these areas, the abnormalreticulum cells showed a marked degree of anaplasia.

RELATIONSHIP BETWEEN THE HISTOLOGICALAPPEARANCES AND SURVIVAL

The original biopsy material was not available forstudy in 15 of the 302 patients, but Hodgkin's diseasewas confirmed by later biopsy, or on necropsy

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R. M. Cross

findings. In 287 patients, the diagnosis of Hodgkin'sdisease was established on examination of the lymphgland, on average, within 14 days of presentation ofthe illness. To determine the incidence of the disease,all patients who presented before January 1967 wereaccepted in the series.On histological appearances, each patient was

allocated to one of the seven types, the distributionof which is summarized in Table III.

TABLE III287 CASES WITH HISTOLOGICALLY PROVEN HODGKIN'SDISEASE ON ORIGINAL BIOPSY DIVIDED INTO THREE GROUPS

AND SUBDIVIDED INTO TYPES1Group No. ofPatients

1 ReticularLymphocyticWell differentiatedPoorly differentiated

2 HistiocyticWell differentiatedPoorly differentiated

3 FibroblasticWell differentiatedPoorly differentiatedNo original slidesTotal

200 (70%)26 (9%)77 (27%)97 (33%)

39 (13 %/)23 (8%)16 (6%)

48 (17%)36 (13%)12 (4%)

15287 302

'The remaining 15 cases were diagnosed as Hodgkin's disease on alater biopsy or at necropsy.

The reticular group, with 200 (70 %) patients, wasthe largest, followed by the nodular sclerosis groupwith 48 (17%) patients, and the histiocytic groupwith 39 (13 %) patients.

Subdivision into the various types showed that thepoorly differentiated reticular type was predominant,with 97 (33 %) patients, followed by the well differ-entiated reticular type, with 77 (27 %) patients, andthe well differentiated nodular sclerosis type with36 (13%) patients.The lymphocytic reticular type, with 26 (9 %)

patients, is similar to the incidence ofparagranulomacases in other series (Smetana and Cohen, 1956;Wright, 1956; Lukes and Butler, 1966; Hanson,1964).

Since 1964, the incidence of nodular sclerosis(Cross, 1968) has increased from 12 to 17% in thepresent series. This may be due to the greaternumber of glands received from females over thepast three years.More recent understanding of the correlation

between histology and prognosis is associated withrealization of the significance of lymphocytes andfibrous tissue. The relationship of lymphocyticproliferation to a favourable prognosis was firstemphasized by Rosenthal (1936), accepted univer-sally in the 'paragranuloma'.cases of Jackson andParker (1944) and in the 'lymphocytic predominance'cases of Lukes and Butler (1966).

1002;46

5O0

0 5 10 15 20Years after presentation

FIG. 19. Cumulative curves for the various types ofHodgkin's disease. I Poorly differentiated reticular;2 poorly differentiated histiocytic; 3 poorly differentiatednodular sclerosis; 4 well differentiated reticular; 5 welldifferentiated nodular sclerosis; 6 well differentiatedhistiocytic; 7 lymphocytic reticular.

Fibrosis, in general, has long been recognized asan integral part of the lymph gland appearance inthe evolution of Hodgkin's disease (Jackson andParker, 1944; Smetana and Cohen, 1956) and thereseems little doubt that fibrosis, as seen in a specificnodular pattern (Lukes and Butler, 1966; Hanson,1964; Harrison, 1966; Cross, 1968), plays asignificant part in the survival time.

Little attention has been paid to the presence ofhistiocytes in the lymph glands of patients withHodgkin's disease, although Harrison (1952),Smetana and Cohen (1956), Wright (1956), andSymmers (1958) made occasional references tosarcoid-like features of Hodgkin's disease. Lukesand Butler (1966) emphasized the association oflymphocytes with reactive histiocytes in certaincases but, as previously indicated, they referred tocells known as normal reticulum cells and not thehistiocytes seen in sarcoidosis. Histological appraisalof the glands in this series indicated a relationshipbetween the presence of significant numbers ofepithelioid histiocytes and long survival of thepatient.

Survival figures were estimated by acceptedstatistical methods, and only patients who presentedbefore 1 January 1965 were included. The cumulativesurvival method was used, and results are shown inFigure 19. The curves of lymphocytic reticular, welldifferentiated histiocytic and well differentiatednodular sclerosis types are similar and distinct fromthe curve of the well differentiated reticular type;the curves of all three poorly differentiated typesshow a similar steep gradient.

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TABLE IVSURVIVAL RATES IN 246 PATIENTS W1TH HISTOLOGICALLY PROVEN HODGKIN'S DISEASE DYING OR PRESENTING BEFORE

1 JANUARY 1965Two-year Survival

Total No. No. No.No. Dead Followed Surviving

Up Two Years

Five-year Survival 10-year Survival

No. No. No. No.Followed Surviving Followed SurvivingUp Five Years Up 10 Years

15-year Survival

No. No.Followed SurvivingUp 15 Years

Reticular GroupLymrphocyticWell differentiatedPoorly differentiated

Histiocytic GroupWell differentiatedPoorly differentiated

Nodular Sclerosis GroupWell differentiatedPoorly differentiatedTotal

227188

86088

227188

22(100%) 21 21 (100%) 15 11 (73%) 1070 (98 %) 62 28 (45%) 47 Nil 3818 (20%) 80 Nil 64 Nil 53

16 6 16 16 (100%) 1510 10 10 6 (60%) 8

2811

246

1811

201

2811246

28 (100%) 236 (54%) 8

166 (67%) 217

3 (30%)NilNil

15 (100%) 12 7 (58%) 4 1 (25%)Nil 6 Nil 2 Nil

20 (87%) 16 8 (50%) 12 4(33%)Nil 6 Nil 2 Nil84 (38%) 166 26 (16%) 121 8 (7%)

The two-, five-, 10-, and 15-year survival rates(Table IV) show that within each group the survivalrates for the well differentiated types are significantlyhigher than the survival rates for the poorly differ-entiated types.The two-year survival rate for the poorly differ-

entiated reticular type is significantly lower (at the5% confidence level) than the survival rate for thepoorly differentiated histiocytic and nodular sclerosistypes combined.The five-year survival rate for the well differ-

entiated reticular type is significantly lower than thesurvival rates for the well differentiated histiocyticand nodular sclerosis types.There is no significant difference in the survival

rate between the lymphocytic reticular type and thewell differentiated histiocytic type and the welldifferentiated nodular sclerosis type.

In the lymphocytic reticular type the two-year andfive-year survival rate of 100 %, the 10-year rate of73 %, and the 15-year rate of 30% support the viewthat there is a good prognosis in cases which showlarge numbers of lymphocytes. This is also demon-strated in the 100% two-year survival rate of thewell differentiated types, compared with the highest(60%) two-year survival rate in the poorly differ-entiated types.

There is a significant relationship betweensurvival time and the presence of histiocytes andfibrous tissue, and, although lymphocytes are not sonumerous in the well differentiated histiocytic andnodular sclerosis types, as in the lymphocyticreticular type, all three types show a similarexcellent prognosis in the five-, 10- and 15-yearsurvival rate. The prognosis in all three poorlydifferentiated types is poor, and, although thenumbers of poorly differentiated histiocytic andnodular sclerosis types are small, there is somesuggestion that they have a slightly better prognosisthan the poorly differentiated reticular type.

The proposed histological classification dividesHodgkin's disease into more homogeneous groupsfrom the point of view of prognosis as follows:

Group

Reticular Histiocytic Nodular Sclerosis

Lymphocytic(Paragranuloma)Well differentiated Well differentiated Well differentiatedPoorly differentiated Poorly differentiated Poorly differentiated

Multiple biopsies of the same patient, taken atvarious intervals during the course of the illness,indicated the tendency to maintain group specificity.In each case there was a gradual depletion of thenumbers of lymphocytes and increase in abnormalreticulum cells, and the latter, in time, showed amore anaplastic appearance. The progress, therefore,was always toward the poorly differentiated in eachgroup and never the reverse.From these findings it is considered that histo-

logical assessment of the lymph gland in Hodgkin'sdisease can make a valuable contribution in assessingprognosis. Further improvement can be achieved bya combination of histological and clinical findings;this will be the subject of a future communication.

I wish to express my thanks to Professor C. V. Harrison,Air Vice-Marshal Sir Peter Dixon, Air Vice-MarshalW. P. Stamm, Wing Commander P. J. Stevens, andSquadron Leader A. W. McCracken for their helpfuladvice and criticism. I am grateful to Miss D. Lindsay,Flight Sergeant P. Mulhall, and Mrs Pearce for theclerical and administrative help, and to the Director-General of Medical Services, Royal Air Force, forpermission to publish.

REFERENCES

Aisenberg, A. C. (1964). New Engl. J. Med., 270, 508, 565 and 617.Cross, R. M. (1968). J. clin. Path., 21, 303.Dawson, P. J., and Harrison, C. V. (1961). Ibid., 14, 219.

Type of Hodgkin'sDisease

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Franssila, K. O., Kalima, T. V., and Voutilainen, A. (1967). Cancer(Philad.), 20, 1594.

Gall, E. A., and Mallory, T. B. (1942). Amer. J. Path., 18, 381.Greenfield, W. S. (1878). Trans. path. Soc. Lond., 29, 272.Hanson, T. A. S. (1964). Cancer (Philad.), 17, 1595.Harrison, C. V. (1952). J. Path. Bact., 64, 513.-(1966). Recent Advances in Pathology, 8th ed. Churchill, London.Hilton, G., and Sutton, P. M. (1962). Lancet, 1, 283.Hodgkin, T. (1832). Med. chir. Trans., 17, 68.Jackson, H., Jr, and Parker, F., Jr (1944). New Engl. J. Med.,

230, 1; 231, 35, and 639.- (1947). Hodgkin's Disease and Allied Disorders. Oxford

University Press, New York.Karnofsky, D. A. (1966). Cancer Res., 26, 1090.Letterer, E. (1924). Frankfurt. Z. Path., 30, 377.Lukes, R. J. (1963). Amer. J. Roentgenol., 90, 944.-, and Butler, J. J. (1966). Cancer Res., 26, 1063.Lumb, G. and Newton, K. A. (1957). Cancer (Philad.), 10, 976.

Marshall, A. H. E. (1956). In An outline of the Cytology and Path-ology of Reticular Tissue, p. 20. Oliver and Boyd, Edinburgh.

Maximow, A. A. (1932). In Special Cytology, Vol. 2, p. 610. Edited byE. V. Cowdry. Hoeber, New York.

Peters, M. V. and Middlemiss, K. C. H. (1958). Amer. J. Roentgenol.,79, 119.

Pullinger, B. D. (1932). In Rose Research on Lymphadenoma,p. 117. By T. Horder et al. John Wright, Bristol.

Reed, D. M. (1902). Johns Hopk. Hosp. Rep., 10, 133.Robb-Smith, A. H. T. (1938). J. Path. Bact., 47, 457.Rosenthal, S. R. (1936). Arch. Path, 21, 628.Smetana, H. F., and Cohen, B. M. (1956). Blood, 11, 211.Sternberg, C. (1898). Z. Heilk., 19, 21.Symmers, W. St. C. (1958). In Cancer, Vol. 2. p. 448. Edited by R. W.

Raven. Butterworth, London.Wilks, S. (1865). Guys Hosp. Rep., 11, 56.Wright, C. J. E. (1956). Cancer (Philad.), 9, 773.

The January 1969 Issue

THE JANUARY 1969 ISSUE CONTAINS THE FOLLOWING PAPERS

Automation in the laboratory M. G. NELSON

An evaluation of the AutoAnalyzer SMA-4 T. R. J.LAPPIN, A. LAMONT, and M. G. NELSON

A report on experience with an automatic bloodcounting machine A. E. GREEN, V. L. MIDDLETON,K. G. PRENTIS, and A. G. SIGNY

Comparison of the effect of heparin and citrate onplatelet aggregation J. R. O'BRIEN, S. M. SHOOBRIDGE,and w. J. FINCH

Fibrinolytic response to moderate exercise in youngmale diabetics and non-diabetics J. D. CASH andR. C. MCGILL

Transient appearance of fibrinolytic activity at theepithelium of the rat uterus KONSTANTINOS TYMPANIDISand TAGE ASTRUP

Examination by electron microscopy of the San Carlosviruses isolated from children with infectious hepatitisA. J. ZUCKERMAN, R. G. BIRD, LORNA J. DUNKLEY, andG. J. LOVE

Electron microscopic observations on the virus particlesin Herpes simplex encephalitis S. ROY and L. WOLMAN

Acute hepatitis due to Herpes simplex virus in an adultT. H. FLEWETT, R. G. F. PARKER, and w. M. PHILIP

Urinary excretion of glycosaminoglycans in the variousforms of gargoylism G. MANLEY and u. WILLIAMS

Serum globulins and infections in mongolism A. W.GRIFFITHS, P. E. SYLVESTER, and E. MARY BAYLIS

Comparative study of immunological tests for pregnancydiagnosis JOYCE L. BELL

Aberrant glandular polypi of the uterine cervix associatedwith contraceptive pills: Pathology and pathogenesisA. D. T. GOVAN, W. P. BLACK, and JESSIE L. SHARP

Comparative antibacterial activity of hexachlorophanein different formulations used for skin disinfectionJ. W. GIBSON

Use of tissues embedded in epoxy resin for routinehistological examination of renal biopsies w. NOELEASTHAM and W. B. ESSEX

Technical methodsEnumeration of platelets using a model B counterELIZABETH E. MAYNE and JOHN M. CARVILLE

Separation of haemoglobins on cellulose acetate J. KOHN

Apparatus for shell freezing liquids in the standardblood transfusion bottles G. W. R. DIKE, F. E. BEW, andG. G. HOPWOOD

Letters to the Editor

Book reviews

Copies are still available and may be obtained from the PUBLISHING MANAGER,

BRITISH MEDICAL ASSOCIATION, TAVISTOCK SQUARE, w.c.l, price 21s.

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Hodgkin's disease: histological classification and diagnosis