Hepatic Manifestations of Lymphomas

Transcription

1 ANNALS OF CLINICAL AND LABORATORY SCIEN CE, Vol. 14, No. 4 Copyright 1984, Institute for Clinical Science, Inc. Hepatic Manifestations of Lymphomas JAMES J. BIEMER, M.D. Pathology Departm ents, St. Joseph s Hospital, and the University of South Florida, School of Medicine, Tampa, FL ABSTRACT The various hepatic manifestations of malignant lymphomas are discussed as well as the methods employed to detect hepatic involvement in those diseases. Hepatomegaly is infrequent in early Hodgkin s disease and, when present, may represent a nonspecific reactive phenomenon. Hepatomegaly is more common in non-hodgkin s lymphomas and various leukemias and usually represents neoplastic involvement of that organ. Radiographic procedures and liver function studies are unreliable in detecting liver involvement although correlation of the various data increases diagnostic accuracy. Morphological manifestations of these diseases are discussed as well as those methods which are best suited for diagnosis. Introduction In clinical practice, diseases which secondarily involve the liver are at least as important as primary hepatic disorders. This is certainly true of the various hematopoietic malignancies where concomitant hemolytic, inflammatory, catabolic, and direct neoplastic effects can present a diverse array of clinical and laboratory findings. In addition, since direct neoplastic infiltration of the liver by lymphoma signifies Stage IV disease9 and imparts such profound implications upon therapy and prognosis, a great bulk of literature attests to the efforts to understand better the liver s role in various lymphomas and leukemias. Most of the studies related to hepatic involvement by lymphomas have concentrated on staging procedures for Hodgkin s disease (HD). Reported hepatic involvement by HD ranges from approximately five percent at presentation25 to 30 percent during the course of the disease,16,17 and over 60 percent at autopsy.16 The literature related to non- Hodgkin s lymphoma (NHL) and leukemias and the liver is less rep lete but indicates an even higher incidence of hepatic involvement by many of those diseases. A wide variety of modern diagnostic tools have been assembled to evaluate the hepatic and other effects of these diseases. It is the purpose of this paper to explore some of the various clinical manifestations of hepatic involvement by hematopoietic malignancies and to discuss the various methods which have been employed to detect it. Physical Findings Most reports have indicated that hepatomegaly is a relatively uncommon /84/ $01.50 Institute for Clinical Science, Inc.

2 finding in early HD, and that even when present it does not necessarily correlate with the presence of a malignant infiltration of the liver.4,5'7,37,39 Perhaps aptly expressing that view, Levitan et al28 concluded in 1961 that only massive hepatomegaly extending to the pelvic brim could be regarded as signifying HD of the liver. Also, Bagley et al4 5 while indicating that hepatom egaly may be useful in predicting a positive liver biopsy in lym phocytic lym phosarcoma, concluded that such was not the case with HD. F urtherm ore, neith er the presence of B symptoms (defined as: (a) unexplained weight loss of more than 10 percent of the body w eight in the six months previous to admission; (b) unexplained fever with tem peratures above 38 C; and (c) night sweats)9 nor the histological classification of the type of HD could be correlated with a positive biopsy. They frequently found only nonspecific inflammatory changes in such livers and thought that they may represent a reaction to the presence of HD elsewhere in the body, much as is also seen in the liver in association with ulcerative colitis and Crohn s disease. Supporting such a concept that active HD can have an indirect effect on hepatocellular function were the observations of Johnson et al,24 who reported reversion of abnorm al liver function studies to normal following local lymphatic irradiation which did not include the liver. When present, however, hepatomegaly is usually of great significance in HD. For instance, Brinckmeyer et al7 found that of their 34 patients who had hepatomegaly, almost all were either stage III B or IV. While percutaneous biopsy was clearly inadequate in detecting hepatic involvement in those patients, (only 4 of 34), 24 of the remaining 30 soon died, and when 18 of them were studied at postmortem, eight or 44 percent had malignant involvement of the liver. F urthermore, hepatomegaly was correlated MANIFESTATIONS OF LYMPHOMAS with a poor prognosis, namely, at the time of analysis, 79 percent of those with hepatomegaly had died compared with 49 percent of all of their cases. Many authors have stressed the relationship of splenic involvement in HD with the presence of hepatic disease.517,18 25,39 W hile rare exceptions have been reported,18 25 the basic tenant concludes that if the liver is involved with H D, the spleen will also be involved.17,25 Glatstein et al17 have reported many interesting correlates, some of which include: of patients with dem onstrated splenic involvem ent, greater than 50 percent had liver involvement; if the patient s spleen were palpably enlarged, 56 percent had liver involvement; and if the spleen weighed over 400 grams, 70 percent of the livers w ere positive. Furtherm ore, if the spleen were palpable in association with a positive lymphangiogram, there was 100 percent liver involvement. Further support for the correlation of a higher incidence of hepatic involvement when the spleen is known to be positive is the experience of the University of Chicago group27 which adopted a policy of routinely radiating the liver if the patient had definite splenic HD. Follow-up studies have shown fewer hepatic recurrences in patients treated in this manner. Studies of NHL and leukemia indicate that hepatomegaly is present more frequently in those diseases, and that there is a higher correlation with malignant involvement of that organ.5,33,34, In the study of 1269 cases of lymphosarcoma reported by Rosenberg et al36 in 1961, 44 percent of the patients had palpable hepatomegaly. The liver in the group of giant follicle lymphosarcoma cases was most frequently palpable, 66 percent, followed by small cell lymphosarcoma, 47 percent, and reticulum cell sarcoma, 37 percent. Overall, 51 percent of all cases were involved with tumor at postmortem examination and of these 57 per

3 2 5 4 BIEMER cent had been palpably enlarged. On the other hand, illustrative that all enlarged livers do not contain tumor, 39 percent of palpably enlarged livers were devoid of tumor at autopsy. Further support of the greater incidence of hepatomegaly in NHL, was the report of Waldor et al39 in 1980, which indicated that while only one of 136 cases of HD presented with hepatosplenomegaly, five of 32 cases of NHL presented that way. Additionally and as indicated earlier, Bagley et al5 have also concluded that hepatomegaly was useful in predicting positive liver biopsies in lymphocytic lymphoma. Lastly, and demonstrative of the more frequent hepatic involvement in some of the leukemias, was the recent report of Yam et al40 in which eight of 19 cases of hairy cell leukemia had hepatomegaly while all 19 had histological proof of tumor in the liver. Radiographic Studies Of the various radiographic studies that have been used to stage lymphomas in the abdom en, lym phangiography, (LAG), has probably been the most useful.7 11,18,22,27 In concluding that LAG was the single most accurate clinical test for detecting HD below the diaphragm, Larson and U ltm ann27 stressed that it rarely detected disease in the upper abdomen. However, while not directly dem onstrating pathology in the liver, nodal positivity of an LAG has been shown to correlate frequently with hepatic involvem ent. Similarly, Brinckmeyer et al7 showed a direct correlation of a positive LAG with hepatomegaly, but they also stated it was not a prerequisite for involvement of the liver since three livers were found to be positive for HD on biopsy in association with a negative LAG. Glees et al18 also indicated that patients with a positive LAG were likely to have HD affecting their livers and spleens. Harris et al22 concluded that LAG and hepatic scintigraphy were quite accurate in predicting the absence of HD in the liver but felt that no study eliminated the need for an exploratory laparotomy. Com paring th eir results with others and expressing them in predictive values, they demonstrated tremendous variability between LAG results as reported by various institutions. They concluded that the low probability of hepatic involvement by HD made the usefulness of LAG doubtful in that regard. In a study of NHL reported in 1980, Chabner et al11,12 felt that LAG was not only very useful for paraortic lymph nodes, but was also an accurate predictor of extranodal abdominal disease as well. In their series of 170 NHL patients, they found that of those who were stage III with a positive LAG, 81 percent were found at laparotomy to have ascites or lymphoma in the liver or lymph nodes outside the paraortic chain while only 18 percent of patients with a negative LAG had similar findings. They concluded that a positive LAG essentially elim i nated the need for a laparotomy since such patients almost invariably had advanced disease which necessitated chemotherapy. Com puterized tomography (CT) has more recently been evaluated for its ability to detect lymphomatous involvem ent in the abdom en, and its results have usually been com pared with the LAG ,41 Castellino10 reported in a study of 58 patients with HD an impressive sounding 95 percent accuracy in detecting liver involvement which was undoubtedly due to the true low incidence of disease in the liver. When looking at the sensitivity of the test, i.e., its ability to detect disease when it was truly present, however, its rate was a very unimpressive 25 percent. Chabner et al11 in their study of NHL similarly concluded that CT while quite accurate in lymph nodes, had a high false negative rate in extranodal tissues. In the study of 160

4 patients with both HD and N HL.15 CT was found to com pare favorably with LAG in detecting involvement of abdominal and pelvic lymph nodes and actually provided additional information about high abdominal nodes. Computerized tomography was poor in its ability to detect both hepatic and splenic lesions and, in fact, was less successful in simply detecting hepatomegaly than physical examination alone. Computerized tomography demonstrated focal hepatic lesions in 10 percent of the NHL and three percent of the HD patients, but Ellert and K reel15 concluded CT was not very helpful in detecting disease of the liver or spleen. Isotopic scans of the liver and spleen, particularly those utilizing 67 Gallium- Citrate, have also been extensively evaluated in HD, NHL, and various leukemias '20,27, These reports have indicted that there is an unacceptably high error rate owing to obscuration by the normal accumulation of gallium in the liver, spleen, colon, and bone, and its usual failure to detect filling defects. In their study of NHL, Greenlaw et al20 indicted that false positives were unusual, but stressed the high false negative rate. There was a tendency for histiocytic and mixed cellular lymphomas to be more often positive than lymphocytic lymphomas. MANIFESTATIONS OF LYMPHOMAS 25 5 Liver Function Tests Many attempts have been made to correlate alteration of liver function tests with the presence of hepatic lesions in HD and NHL.2-3 4'5 7'11'17-18'19'24'26-36These reports have ranged from a conclusion that they were dishearteningly unreliable or of no value with an unacceptably high error rate,3, to the more optim istic report of Gobbi et al19 in They indicated that hepatic involvement in HD was found to be singly related to serum albumin «3.5 g per dl, serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamic pyruvate transaminase (SGPT)s= 20 mu per ml, serum alkaline phosphatase (SAP) 5^210 mu per ml, bromsulphalein (BSP) retention at 45 min s?6.5 percent, and erythrocyte sedim entation rate (ESR) 3=51 mm at one hour as well as the results of liver isotopic scans and liver and/or spleen enlargement. They also proposed use of various combinations of these findings which they indicated correctly predicted liver involvement in 89.5 percent of cases. Alkaline phosphatase seems to have been the most extensively studied liver function test. Aisenberg et al2 have shown a progressive increase in the percentage of HD patients with elevated SAP as the stage of their disease advanced; thus 14 percent of Stage I & II patients had elevated SAP, 65 percent at Stage III and 81 percent at Stage IV. Aisenberg et al2 with the use of polyacrylam ide gel electrophoresis and Deeble & Goldberg14 with heat stability showed that the SAP was almost always hepatic in origin, although in some patients it was of skeletal origin or a combination of both. In many instances, the elevation of SAP appeared to be nonspecific and not associated with the hepatic lesion of HD. Brinckmyer et al7 in their analysis of 308 HD patients indicated that elevation of SGOT and SAP, even in the early stages of the disease, was associated with a poorer prognosis. Of 10 patients with positive liver biopsies, the associated clinical findings in decreasing order w ere elevation of SAP and SGOT, hepatomegaly, positive LAG, and splenomegaly. However, since half of their total cases had one or more of those findings, no one or combination of them could be regarded as specific for liver infiltration. Furthermore, while 23 of 24 patients with hepatomegaly had elevated SGOT & SAP, these enzymes were elevated in 80 patients in the entire series

5 2 5 6 BIEMER emphasizing the nonspecific nature of the findings. Aisenberg et al2 and Bagley et al4 also discussed the elevation of SAP and BSP retention in association with negative livers in HD, and Johnson et al24 demonstrated reversion to normal of liver function studies following local irradiation therapy to areas other than the liver. They felt that this indicated some indirect or reactive effect on hepatocellular function from active HD located elsewhere in the body. Bromsulphalein retention and SGOT studies have generally been similar to those of SAP.2,4,719 Increased bilirubin is considered unusual in H D,7 although jaundice was present at autopsy in 31 of 115 (27 percent) patients rep orted by Givler et al.16 Also, while a 12.5 percent incidence of jaundice in the 1961 retrospective study of lymphosarcoma was reported, it should be noted that 40 percent of these appeared just prior to death and were largely attributable to intra or extra hepatic obstruction by tumor in an era prior to effective therapeutic agents for lymphoma.36 Other enzymes that have been investigated to evaluate hepatic involvement in lymphomas include; 5-nucleotidase,2,14,26 serum ornithine transcarbamoylase,14 aminotransferases,14 lactic acid dehydrogenase (LD H ),23,26 and alpha glutamyltranspeptidase.26 None of these appear to offer any greater degree of specificity although D eeble & Goldberg14 in their study of 72 patients with HD and NHL found elevated 5-nucleotidase in all 14 patients who either had or would subsequently develop hepatic involvement. In another study of NHL in 1980, Chabner et al11 indicated that lymphomas produce little alteration of hepatic function, and that while peripheral blood counts and liver chemistries may be helpful, they are not reliable indicators of liver involvement. Similarly the recent report of hairy cell leukemia40 which shows histological involvement of the liver in all cases, states that there was poor correlation between liver size, biochemical values and the number of malignant cells in the peripheral blood with the severity of the hepatic neoplastic infiltration. The same was reported for T- cell lymphomas23 where again, despite a high incidence of actual involvement of the liver by tumor, SAP and LDH were of no assistance in identifying such patients. Biopsy Procedures Histological proof of the presence of lymphoma in the liver remains the reference to which all other diagnostic methods are compared. Since the early lesions of HD are usually small, discrete, white nodules,5 it is not surprising that blind percutaneous needle biopsy of the liver has been described as clearly inadequate.4 As m ight be expected, needle biopsies of the liver, taken during visualization by peritoneoscopy, have a significantly greater yield with no increased risk of morbidity over the blind percutaneous m ethod.4,5,6,13,27 Most studies which compare percutaneous biopsy, peritoneoscopy directed biopsy, and laparotomy demonstrate a progressive increase in the diagnostic accuracy of each of these procedures ,31 32 This is, of course, related to the operator s progressive ability to visualize grossly and to biopsy abnormal areas of the liver which are far more apt to yield positive histological results.16,27 The report of Larson and U ltm ann27 strikes somewhat of a discordant note, however, when they point to a senior surgeon s frequent inability to recognize grossly the hepatic lesions of HD, citing six out of eight false positive, and one of 221 false negative impressions at the time of surgery. Nevertheless, the ability to visualize directly the area to be biopsied so positively influences the result that lap

6 aroscopy and laparotomy result in definitely im proved pathologic staging of HD.6 With the advent of more successful chemotherapeutic methods for patients with B symptoms9 or bulky disease, most institutions are now limiting staging laparotomies in HD for those patients who can be expected to benefit from local curative radiation therapy, namely, those with clinically Stage I, II, or III A disease.17,21,31 Since the late complications of chem otherapy include serious second malignancies, however, there will remain a strong impetus to avoid overstaging and, thus, overtreatment in HD. Most likely then, laparotomy with its resultant improved pathologic staging will remain an important tool in the management of select cases of H D.9,17,31,32 The role of laparotomy for staging of NHL is now clarified and essentially relegated to history. There is no longer a place for staging laparotomy in NHL because the biology of these lymphomas suggests that they are systemic proliferations from inception21 as opposed to HD which is generally regarded as a monoclonal neoplasm of unified origin which spreads secondarily by metastasis of preexisting tumor cells largely by contiguous lymphatics.25 Furthermore, since NHL patients are significantly older than HD patien ts,39 mean age of 51.5 years vs years, laparotomy results in more numerous and frequently serious post operative complications following laparotomy. In any event, however, the reports of previous studies again confirm the progressive accuracy of percutaneous biopsy, followed by peritoneoscopy directed biopsy and, lastly, laparotomy for confirming NHL involving the liver.5,11 Bagley et al5 demonstrated an incidence of 76 percent liver lesions in lymphocytic lymphoma while Chabner et al11 found 80 percent in nodular and diffuse poorly differentiated lymphocytic lymphoma. By all techniques, diffuse histiocytic lymphomas showed the lowest incidence of MANIFESTATIONS OF LYMPHOMAS liver involvement. These findings are in keeping with modern concepts of NHL which show a high expectency of Stage III or IV disease at presentation with small cell lymphomas, i.e., well differentiated lymphocytic or small cleaved cell lymphomas of follicular center cell origin, and a higher frequency of more localized Stage I or II diseases at presentation with the large cell or histiocytic lymphomas.30 Morphological Manifestations Since the morphologic expression of the NHL in the liver almost invariably consists of a monomorphous neoplastic infiltration of lymphoid cells similar to those seen in other biopsied tissue, there is usually little difficulty distinguishing a truly neoplastic process from a nonspecific inflam m atory process. However, since the classical histological findings of HD are typically pleocellular and tend to mimic an inflammatory process, there is not infrequently difficulty separating a nonspecific inflammatory process from one that is a true neoplastic infiltrate of HD in small biopsy specimens. Such a distinction is also of great im portance since nonspecific inflammatory lesions found in the liver in HD are more common and less ominous than a true malignant infiltration.4,38 While an earlier report28 based upon autopsied cases indicated that 86.5 percent of the hepatic lesions of HD were diffuse and only a minority were nodular, later reports based upon laparoscopic or laparotomy findings5 indicate that the early lesions of HD are usually focal and consist of small w hite nodules and papules. As indicated earlier, biopsies taken from those sites are far more apt to be positive than random biopsies, although occasional positive microscopic findings are encountered from biopsies of livers that are described as totally normal in gross appearance.

7 25 8 BIEMER In a recent report of 459 liver biopsies in 308 patients with H D,38 typical diagnostic Hodgkin infiltrates were found in only 2.4 percent of biopsies while lesions suspect of HD were recognized in 1.7 percent. The most common lesion in 47 percent of the biopsies was a nonspecific, slight to moderate lymphocytic infiltrate in the portobiliary space w ithout abnormal histiocytic cells. Focal hepatocellular necrosis was encountered in 19 percent of patients while nondiagnostic plemorphic cell infiltrates and epithelioid cell granulomas were found in four percent and two percent of patients, respectively. The authors concluded that the liver was frequently a site of nonspecific changes which were not indicators of malignancy and which did not appear to have any significance in the course of the disease. O ther studies have addressed the difficulty in interp retin g such lesions and advised strategy for separating inflam m atory from neoplastic Hodgkin infiltrates in the liver.4'8,16 29 Further recognition of the importance of the distinction between true Hodgkins and nonspecific infiltrates is found in the Report of the Committee on Histopathological Criteria Contributing to Staging of Hodgkin s Disease35 making recommendations for interpreting staging liver biopsies in patients with histologically proven HD. Since the amount of tissue available for study is usually small, and Sternberg-Reed (SR) cells can usually be seen only if they are numerous, serial sections should be examined if possible. If, after examining serial sections, there is a portal triad cellular infiltrate characteristic of HD but having only mononuclear cells with nuclear features of SR cells, the process should be regarded as indicative of hepatic involvement. If on the other hand, there are only atypical histiocytes or reticulum cells which fall short of these criteria within one of the characteristic cellular environments of HD, the process should be reported as suggestive of H D. The clinician should utilize this information in conjunction with all other available data in arriving at a decision as to whether such patients should be considered as having Stage III or Stage IV disease. So called nonspecific infiltrates should not be regarded as suggestive of HD. Caution is indicated in patients in whom the infiltrates are relatively extensive or massive. Such infiltrates in the presence of HD elsewhere are suspicious of liver involvement; yet, in the absence of at least atypical histiocytes (reticulum cells), an unequivocal histiological diagnosis cannot be made. The finding of non-caseating sarcoidlike granulomas in approximately 10 to 15 percent of cases of HD is interesting. While the granulomas may be intimately associated with the neoplastic lesion of HD, their presence alone does not constitute evidence of HD in any particular organ. Of undetermined etiology and not correlated with intradermal antigen reactivity, their presence has, however, been associated with an improved survival at all stages of HD as compared to cases without them.37 Summary Hepatomegaly is uncommon in early HD, and only when massive in nature can it be concluded in itself to be indicative of involvement by HD. It is suggested that hepatom egaly may frequently be a reactive manifestation to HD elsew here in the body. W hen present, however, hepatomegaly is usually indicative of a more advanced HD and associated with a poorer prognosis. Inform ation regarding the spleen is helpful in predicting the presence or absence of HD in the liver; that is, if the spleen is involved with HD, over 50 percent of the livers will also be positive. In the NHL, hepatomegaly is even more common than with HD and is most frequently seen in the small cell lymphomas

8 and less frequently in the large cell varieties. Also w hen hepatom egaly is present in NHL, it is more often associated with neoplastic infiltration than in HD. The liver remains a relative blind-spot in so far as the various rediographic studies are concerned. Clinical detection of hepatomegaly has often been more accurate than many of these procedures. Lymphangiography while very useful in determining nodal disease in the lower abdomen, is not helpful in the upper abdomen. Computerized tomography scanning seems to oifer an advantage also in being able to evaluate high abdominal nodes, but it is relatively insensitive to hepatic disease. Radioisotopic scans occasionally accurately dem onstrate hepatic pathology of lymphomas; however, they lack sensitivity and suffer from many false negatives. Studies in NHL tend to be similar. Numerous liver function studies have been evaluated and none are specific or very helpful. While they tend to be frequently positive in advanced stages of disease and in association with hepatomegaly, there are too many exceptions to allow specific conclusions regarding hepatic involvement by lymphomas. Since the early manifestations of HD and the large cell lymphomas tend to be nodular, only those biopsies which allow direct visualization, i.e., laparoscopy or laparotomy, can reliably detect hepatic disease. The small cell NHL and leukemias tend to be more diffusely infiltrative in the liver and, hence, blind percutaneous biopsies have a greater tendency to provide reliable results in those instances. References 1. A d l e r, S., P a r t h a s a r a t h y, K. L., B a h s h i, S. P., et al.: Gallium-67-citrate scanning for the localization and staging of lymphomas, J. Nucl. Med. 16: , MANIFESTATIONS OF LYMPHOMAS A i s e n b e r c, A. C., K a p l a n, M. M., R i e d e r, S. V., et al.: Serum alkaline phosphatase at the onset of Hodgkin s disease. Cancer 26: , A pp el gvi st, P. and Sa l m o, M.: Staging laparotomy in Hodgkin s disease. Intern. Surg. 67: , B a g l e y, C. M., Jr., R o t h,j. A., T h o m a s, L. B., et al.: Liver biopsy in Hodgkin s disease. Ann. Intern. Med. 76: , B a g l e y, C. M., Jr., T h o m a s, L. B., Jo h n s o n, R. E., et al.: Diagnosis of liver involvement by lymphoma: Results in 96 consecutive peritoneoscopies. Cancer 31: , B e r e t t a, G., Spinelli, P., R ilke, F., et al.: Sequential laparoscopy and laparotomy combined with bone marrow biopsy in staging Hodgkin s disease. Cancer Treat. Rep. 60: , B r i n c k m e y e r, L. M., Sk o v s g a a r d, T., T h i e d e, T., et al.: The liver in Hodgkin s disease. I. Clinicopathological relations. Eur. J. Cancer Clin. Oncol. 18: , B r o w n, R., G illett, R., St a n s f e l d, A., et al.: The timing of liver biopsy during staging laparotomy for Hodgkin s disease. Clin. Oncol. 7:99-103, C a r b o n e, P. P., K a p l a n, H. S., M u s s h o f f, K., et al. : Report of the Committee on Hodgkin s D isease Staging Classification. Cancer Res 31: , C a s t e l l i n o, R. A.: Imagining techniques for staging abdominal Hodgkin s disease. Cancer Treat. Rep. 66: , C h a b n e r, B. A., F is he r, R. I., Y o u n g,r. C., et al.: Staging of non-hodgkin s lymphoma. Semin. Oncol. 7: , C h a b n e r, B. A., Jo h n s o n, R. E., Y o u n g, R. C., et al.: Sequential non-surgical and surgical staging of non-hodgkin s lymphoma. Ann. Intern. Med. 85: , C o l e m a n, M., L i g h t d a l e, C. J., V i n c i g u e r r a, V. P., et al.: Peritoneoscopy in Hodgkin s Disease. Confirmation of results by laparotomy. J. Am. Med. Assoc. 236: , D e e b l e, T. J. and G o l d b e r g, D. M.: Assessment of biochemical tests for bone and liver involvem ent in malignant lymphoma patients. Cancer 45: , E l l e r t,j. and K r e e l, L.: The role of computed tomography in the initial staging and subsequent management of the lymphomas. J. Comput. Assist. Tomogr. 4: , G iv le r, R. L., B r u n k, S. F., H ass, C. A., etal.: Problems of interpretation of liver biopsy in Hodgkin s Disease. Cancer 28: , G l a t s t e i n, E., G u e r n s e y, J. M., R o s e n b e r g, S. A., et al.: The value of laparotomy and splenectomy in the staging of Hodgkin s disease. Cancer 24: , G l e e s, J. P., B a r r, L. C., M c E l w a i n, T. J., et al.: The changing role of staging laparotomy in Hodgkin s disease: A personal series of 310 patients. Brit. J. Surg. 69: , 1982.

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