thediagnosis of hodgkin's disease in surgically excised spleens · thediagnosis...

J. clin. Path., 1972, 25, 294-300

The diagnosis of Hodgkin's disease in surgicallyexcised spleensGEOFFREY FARRER-BROWN, M. H. BENNETT, C. V. HARRISON,YVONNE MILLETT, AND A. M. JELLIFFE

From the Bland-Sutton Institute ofPathology and the Radiotherapy Department, Middlesex Hospital,London, and the Pathology Departments of the Mount Vernon Hospital, Northwood, Middlesex, and theRoyal Postgraduate Medical School, London

SYNOPSIS A series of 44 spleens removed from patients with Hodgkin's disease before treatmenthas been reviewed. The difficulties encountered in detecting foci of Hodgkin's tissue and thehistological features and characteristics of early invasion are described.

In a proportion of cases of Hodgkin's disease failureof treatment is due to the presence of undetected fociof disease outside the treated area, and in particularfoci in the spleen. To overcome this difficultyGlatstein, Guernsey, Rosenberg, and Kaplan (1969),Glatstein, Trueblood, Enright, Rosenberg, andKaplan (1970), and Jelliffe, Millett, Marston,Bennett, Farrer-Brown, Kendall, and Keeling (1970)have recommended laparotomy with splenectomybefore the start of therapy. This permits accurateassessment of the extent of the disease and con-sequently proper therapeutic management and italso removes a focus of disease in an organ that isdifficult to treat. There is reason to believe thatsplenectomy in appropriate cases improves thechances of long-term survival and consequently it islikely to be undertaken more often, with the resultthat pathologists will be asked to study spleens earlyin the course of the disease. It is the purpose of thiscommunication to draw attention to the difficultiesin diagnosis that we have encountered in a series of44 spleens,' removed as a diagnostic procedure frompatients with Hodgkin's disease at the Middlesexand Harefield Hospitals and the Royal PostgraduateMedical School between April 1970 and May 1971.The histological appearances in early splenic in-volvement are varied but this study has revealedcertain characteristic patterns.

Method

All spleens were weighed, measured, and cut into

'This series of spleens forms part of the material submitted to theNational Lymphoma Investigation (Clinical Cancerthermpy Co-operative Group) which commenced in February 1970.

Received for publication 21 October 1971.

two or more slices, depending on size, to obtain goodfixation. When fixed they were examined grossly andif no obvious deposits were seen the spleens weresliced as thinly as possible (2-3 mm) in order todetect single minute foci. If no abnormality wasapparent the general size of the Malpighian bodieswas assessed and blocks taken that included thelargest Malpighian bodies as these were the mostlikely sites of early involvement. Sections werestained by routine histological methods.

Results

Details of the patients, with involved and uninvolvedspleens plus the splenic weight and the histologicaltype of Hodgkins's disease (Rye Classification,Lukes, Craven, Hall, Rappaport, and Ruben, 1966)of the original lymph node, are shown in Tables Iand II.The age range of the 32 male and 12 female

patients was 11-77 years with a median of 30 years.Twenty-two uninvolved spleens weighed between100 and 690 g while the weights of the 22 spleenscontaining Hodgkin's tissue ranged from 77 to 870 g(Fig. 1). The median weight of involved spleens(304 g) was 112 g heavier than those that were un-involved (192 g). A normal weight did not excludeinvolvement and an abnormally heavy spleen wasoften uninvolved by malignant lymphoma.

In 14 of the 22 involved spleens abnormal noduleswere easily detectable on macroscopic examinationbut in two spleens only single nodules 3 mm and2 mm respectively were present (Fig. 2). A furtherthree spleens contained only two to five small fociup to 7 mm diameter. Three specimens with onlyslight prominence of the Malpighian bodies (Fig. 3)

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The diagnosis of Hodgkin's disease in surgically excised spleens

Rye Classification of Case No. Patient Hospital SpleenOriginal Lymph Node Weight

Initials Sex Age (g)

Lymphocytic predominant 4 WW M 55 Middlesex 55025 AL M 56 Royal Postgraduate Medical School 66028 MH F 37 Middlesex 28036 RM M 52 Harefield37 AS M 75 Harefield39 SB F 45 Middlesex 229

Nodular sclerotic 1 MP M 16 Middlesex 3858 KE M 15 Middlesex 254

1 1 CB M 59 Middlesex 17512 GC M 23 Middlesex 87013 Pi F 38 Middlesex 14914 CM M 28 Middlesex 21324 RB M 31 Middlesex 48026 DC M 35 Middlesex 20638 CC F 24 Middlesex 39443 DE M 47 Royal Postgraduate Medical School 31344 HC M 46 Middlesex 495

Mixed cellularity 7 TMG M 25 Middlesex 7715 JB M 40 Middlesex 37029 RR M 22 Middlesex 25035 EM M 58 Middlesex 50541 FC M 77 Royal Postgraduate Medical School 295

Table I Details ofpatients with involved spleens

Rye Classification of Case No. Patient Hospital SpleenOriginal Lymph Node Weight

Initials Sex Age (g)

Lymphocyte predominant 33 AM M 21 Middlesex 195

Nodular sclerotic 2 EB M 22 Middlesex 1553 CF F 36 Middlesex 2559 SL F 22 Middlesex 14010 MW F 11 Middlesex 10016 SM F 24 Middlesex 25517 EM F 20 Middlesex 20518 RP M 19 Middlesex 32119 EG F 19 Middlesex 20420 AR M 30 Middlesex 16022 AP F 29 Middlesex 10531 SZ M 26 Middlesex 16342 WW F 60 Middlesex 165

Mixed cellularity 5 DB M 24 Middlesex 3606 MS M 34 Middlesex 399

21 FK M 33 Middlesex 69023 BS M 15 Middlesex 42027 JM M 28 Royal Postgraduate Medical School 18030 JC M 37 Middlesex 15332 KB M 35 Middlesex 16434 AS M 30 Middlesex 34040 JO M 57 Middlesex 125

Table II Details ofpatients with uninvolved spleens

and no macroscopic discrete foci proved to be (1966). In this present study no obvious correlationpositive on histological examination. was found between the lymph node histological typeThe original lymph node biopsy from each and the likelihood of involvement of the spleen by

patient had been classified histologically by three of Hodgkin's disease.the authors (M.H.B., G.F.-B., and C.V.H.) inde- Six of the seven patients with lymphocyticpendently according to the Rye modification (Lukes predominant disease in the lymph nodes, 11 of 23et al, 1966) of the Lukes and Butler classification patients with nodular sclerotic Hodgkin's disease,

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Geoffrey Farrer-Brown, M. H. Bennett, C. V. Harrison, Yvonne Millett, and A. M. Jelliffe

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Fig. 2 The microscopical appearance ofa single focusofHodgkin's tissue in a 213 g spleen. Compare with theuninvolved Malpighian bodies. H and E x 15

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Fig. 1 The weights of uninvolved spleens and thoseinvolved by Hodgkin's tissue.

Fig. 3 A spleen, after fixation, with prominentMalpighian bodies all of which proved to be positive onhistological examination. x 1-5.

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Fig. 4 Abnormal histiocytic cells present in the peri- Fig. 5 A normal reversed follicle containing a reactivearteriolar area at the top of the figure and at the centre. The immature cells are peripheral to the darkperiphery of the adjacent Malpighian body. H and E staining mature cells surrounding the reactive centre.x 96. H and E x 60.

Fig. 6 Cluster of epithelioid histiocyticcells seen in a spleen involved byHodgkin's disease. H and E x 186.

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Fig. 7 'Lipophage' granulomata in a Malpighian body Fig. 8 'Sarcoid-like' granulomata seen in an uninvolvedin an uninvolved spleen. H and E x 168. spleen. H and E x 66.

Fig. 9 Enlarged and ill definedMalpighian bodies involved byHodgkin's disease adjacent to normalMalpighian bodies at the right of thefigure. H and E x 24.

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Fig. 10 Generalized enlargpment of Malpighian bodiesdue to diffuse infiltration by Hodgkin's tissue. Themagnification is similar to Figure 9. H and E x 24.

and five of 14 with mixed type disease had involvedspleens. There were no patients with lymphocytic-depleted Hodgkin's disease in the original lymphnode in this series of splenectomies.An attempt has been made to apply the Rye

histological classification to the appearances ofHodgkin's tissue in the spleen because early in thisstudy it became apparent that the characteristicfeatures of lymphocytic predominance or depletion,mixed cellularity type, and even nodular sclerosismay be present. In this series just over 45% of caseswith involved spleens had the same histological typeof Hodgkin's disease in the spleen as in the originallymph node. In 27% a lymphocytic-depleted appear-ance with diffuse fibrosis was present in the spleenalthough the lymph node histology was lymphocyticpredominant, nodular sclerotic, or mixed in type. Incontrast five of the 16 patients with nodular scleroticor mixed cellularity lymph node histology showed alymphocytic-predominant picture in the spleen.

Microscopical examination of the three spleenswith no detectable gross abnormality except slightly

prominent Malpighian bodies showed involvementof these lymphoid foci by Hodgkin's disease of thelymphocytic predominant type. In one specimenabnormal cells were present throughout the whitepulp but in other instances they were confined to theperiarteriolar areas and to the periphery of thelymphoid follicles (Fig. 4). When involvement wasconfined to these areas diagnostic Reed-Sternbergcells were relatively easy to detect in the mixedcellularity type of disease, but in the lymphocytic-predominant type of disease the only abnormalitywas often merely a rim of histiocytes and carefulsearch was needed to detect Reed-Stemnberg cells.These appearances must be distinguished from thereversed follicle often seen in normal spleens (Fig. 5).In three of the eight spleens with involvement bylymphocytic-predominant disease clusters of epi-thelioid histiocytes (Fig. 6), occasionally with giantcells, were present within both the red and whitepulp. These histiocytic clusters contrasted with lipo-phage (Fig. 7) or sarcoid-like granulomata (Fig. 8)seen in other involved and uninvolved spleens.

Involved Malpighian bodies were nearly alwaysenlarged compared with normal and were fairlyeasily detectable when adjacent to normal Mal-pighian bodies (Fig. 9), but it was less obvious whenall lymphoid follicles showed uniform early involve-ment by Hodgkin's tissue (Fig. 10). A number ofspleens showed that large foci of Hodgkin's tissueformed as a result of coalescence of the invadedMalpighian bodies.

Discussion

Careful gross examination of all spleens is essentialto detect the presence of Hodgkin's disease. Initialslicing of the spleen is necessary to ensure adequatefixation. There is no absolute correlation betweenspleen weight and involvement of the organ. This isin agreement with the findings of Kadin, Glatstein,and Dorfman (1971) who, in their clinicopathologicalstudy of 117 untreated patients subjected to laparo-tomy, reported on the frequency of Hodgkin'sdisease in spleens of normal weight and size. Largespleens may not be involved while small spleens maycontain foci of lymphoma. In general the larger thespleen the more obvious are the nodules of Hodgkin'stissue but all spleens which are not obviously in-volved must be sliced as thinly as possible to detectminute foci. On occasion the only suspicious macro-scopic finding will be slightly prominent Malpighianbodies which may appear slightly whiter thannormal. If no gross abnormality is detectable theblocks taken should contain the largest Malpighianbodies visible in order to exclude early microscopicinvasion.

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This study has shown the variation in histologicalappearances that may be present in early involve-ment of the spleen by Hodgkin's disease. Involve-ment appears to begin in the periarteriolar area andperiphery of the Malpighian bodies after which thislymphoid tissue becomes diffusely infiltrated. At thisearly stage detection of the lymphocytic and histio-cytic type of disease may be difficult, particularly ifabnormal cells are confined to the periphery of theMalpighian bodies rather than involving themdiffusely. The above features should not be confusedwith two benign appearances of the lymphoid tissueof the spleen, neither of which show any correlationwith the likelihood of involvement of the organ byHodgkin's disease. The first is the 'reversed follicle',often seen in normal spleens, when the Malpighianbodies contain central, mature lymphocytes sur-rounded by less mature cells (Klemperer, 1938), andsecondly there is the presence of definite reactivecentres in the Malpighian bodies.Another diagnostic problem is the distinction

between various types of granulomata seen in thespleen. It is well known that in lymph nodes with thelymphocytic-predominant type of Hodgkin's diseaseclusters of epithelioid histiocytes may give an im-pression of 'sarcoid-like' granulomata. This type ofHodgkin's granuloma was seen in the spleens in thisstudy involved by either the lymphocytic-predomin-ant or nodular-sclerotic types of disease. Theseclusters may be present within both the white andred pulp and, as diagnostic cells are usually veryscanty, differentiation from classical sarcoid-likegranulomata or lipophages may prove difficult. In thelatter the presence of fat globules usually makes thediagnosis simple but occasionally globules areminimal and the foci of lipophages resemble 'epi-thelioid' granulomata with foreign body type giantcells. The cause of the lipophages is unknown. Thesignificance of classical 'sarcoid-like' granulomata ismore difficult to assess and in two uninvolved spleensin this series their significance remains obscure, butin agreement with Kadin et al (1971) we do notconsider that they represent Hodgkin's disease,although possibly they may be a reaction to the con-dition. One was a 660-g spleen from an Egyptian boywho had a mixed cellularity type of Hodgkin'sdisease in the right epitrochlear lymph nodes and hadlived all his life in Egypt. The other was a 225-g spleenfrom an English girl with nodular sclerotic Hodgkin'sdisease in a right cervical lymph node. In neither ofthese cases could definite Hodgkin's tissue be foundin the spleens.No correlation was found between the histological

type of Hodgkin's disease in the original lymph nodeand the likelihood of involvement of the spleen.Histological classification of the type of Hodgkin's

disease in the spleen proved relatively easy, and it isinteresting that in nearly half of cases with involvedspleens the same histological type was present in thespleen as in the lymph node. A more lymphocyticpredominant type of histology in the spleen com-pared with the lymph node was found only when in-volvement of the spleen was early. It is possible,however, that in some of these cases nodular sclerosisin the spleen had not yet become apparent as fibrousbands were not seen in early involvement of thisorgan. At this stage of involvement the diagnosis ofnodular sclerosis may have to be made solely on thecellular component and the presence of lacunar cells.In just over a quarter of the spleens the histologicaltype was worse in the spleen with features of lympho-cytic depletion and yet in all cases laparotomy wasperformed as a diagnostic procedure within a fewmonths of the initial diagnostic lymph node biopsy.Follow up of these patients will be particularlyinteresting as at the present time the prognosticsignificance of histological progression of the diseaseis unknown.

The authors wish to thank the many clinicians andsurgeons who referred patients for investigation andtreatment. We are very grateful to Miss JennyAbrahams, Miss Eileen Green, and Miss Linda Deanfor secretarial assistance. Financial support for thiswork and for the Clinical Cancertherapy CooperativeGroup has been generously provided by Eli Lilly &Co, Roche Products Ltd, the J. S. Frazer Trust Fund,the Peggy Russell Memorial Fund, the New CourtCharitable Trust, the Aitchison Charitable Trust, theCancer Research Campaign, and many individualswho have a personal interest in this researchprogramme.

References

Glatstein, E., Guernsey, J. M., Rosenberg, S. A., and Kaplan, H. S.(1969), The value of laparotomy and splenectomy in thestaging of Hodgkin's disease. Cancer (Philad.), 24, 709-718.

Glatstein, E., Trueblood, H. W., Enright, L. P., Rosenberg, S. A.,and Kaplan, H. S. (1970). Surgical staging of abdominalinvolvement in unselected patients with Hodgkin's disease.Radiology, 97, 425-432.

Jelliffe, A. M., Millett, Y. L., Marston, J. A. P., Bennett, M. H.,Farrer-Brown, G., Kendall, B., and Keeling, D. H. (1970).Laparotomy and splenectomy as routine investigations in thestaging of Hodgkin's disease before treatment. Clin. Radiol.,21, 439-445.

Kadin, M. E., Glatstein, E., and Dorfman, R. F. (1971). Clinico-pathologic studies of 117 untreated patients subjected tolaparotomy for the staging of Hodgkin's disease. Cancer(Philad.), 27, 1277-1294.

Klemperer, P. (1938). The spleen. Section XXI. In Handbook ofHaematology, Vol. III, Sect. XXI, edited by H. Downey,p. 1661. Hoeber, New York.

Lukes, R. J., and Butler, J. J. (1966). The pathology and nomenclatureof Hodgkin's disease. Cancer Res., 26, 1063-1081. (Discussionby H. Rappaport, 1082-1083.)

Lukes, R. F., Craven, L. F., Hall, T. C., Rappaport, H., and Ruben, P.(1966). Report of the Nomenclature Committee. Cancer Res.,26,1311.

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thediagnosis of hodgkin's disease in surgically excised spleens · thediagnosis...

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