Br. J. Cancer (1975) 31, Suppl. II, 237

PATTERNS OF INVOLVEMENT WITH MALIGNANT LYMPHOMA AND IMPLICATIONS FOR TREATMENT DECISION MAKING R. E. JOHNSON, V. T. DEVITA, L. E. KUN, B. R. CHABNER, P. B. CHRETIEN, C. W. BERARD AND S. K. JOHNSON From the Radiation, Medicine, and Surgery Branches and the Laboratory of Pathology,

National Cancer Institute, Bethesda, Maryland 20014, U.S.A.

Summary.-Decision making in cancer therapy has traditionally evolved through careful observation of the clinical course subsequent to various treatment approaches. This method has also served to delineate the wide spectrum of primary manifestations and patterns of biological behaviour characterizing the malignant lymphomata. Marked disparity has been consistently appreciated between the natural history of lymphomata originating in lymph nodes in contrast to those primary in extranodal sites. The former are usually anatomically generalized at diagnosis whereas primary extranodal lymphomata are commonly localized and more closely resemble carcinomata of the respective organs with their propensity for both regional lymphatic extension and haematogenous spread. Prospective staging of 100 consecutive patients with previously untreated malignant lymphoma has been consistent with this past experience in demonstrating the presence of disseminated involvement in the majority of patients. It has also become apparent that reliance upon either clinical or surgical staging of disease extent is often misleading since widespread disease frequently develops even in those patients staged as having localized involvement and thereby treated with local irradiation. High dose, wide field lymphatic irradiation " a la Hodgkin's disease " seldom constitutes appropriate treatment for patients having lymph node presentations of lymphoma. There is rather a need to recognize the importance of systemic treatment for most cases, negating the utility of routine exhaustive staging since treatment decisions cah be based upon readily assessed clinicohistological determinants in the majority of cases.

TREATMENT decision making in cancer management has historically depended upon careful observation of the clinical course subsequent to various therapeutic measures. Trial and error have evolved fairly dependable methods for controlling primary manifestations of many neoplasms, the follow up recording of secondary signs of disease progression thereby delineating the natural history to some degree. Meticulous attention devoted to pretreatment evaluation has reduced dependency of treatment decision-making upon prior clinical experience in Hodgkin's disease. Such diagnostic evaluation, referred to as staging, has well established utility in the process of treatment selection. However, extrapolation of staging

techniques and classifications from Hodgkin's disease to the so-called " nonHodgkin's lymphomata " has been constrained by the marked disparity between these diseases. The intent of this paper is to stress these limitations and to emphasize that the results of staging demand integration with (and interpretation in the light of) other more readily appreciable clinicohistological determinants which correlate with the natural history of disease. MATERIALS AND METHODS

The clinical material providing the data for the prospective analysis consists of the initial 100 consecutive patients with previously untreated malignant lymphoma evaluated collaboratively by the Radiation

238

R. E. JOHNSON EP AL.

TABLE I.-Sequential Diagnostic Studies Table IV included the history and physical used for the Staging of the Malignant examination, routine haematology, standard chest and bone radiographs, and Lymphoma,ta biopsy of clinically obvious lesions such as 1. Detailed history and physical examination 2. Specific studies per history and examination subcutaneous nodules or the aspiration of 3. Complete blood count malignant effusions. Following these 4. Chest radiography with tomograms as needed routine examinations, 37% of the total 5. Metastatic skeletal survey 6. Isotopic studies of bonie and liver-spl3en number were still deemed to have local7. Bone marrow needle biopsy (twice) regional involvement potentially amenable 8. Percutaneous liver biopsy 9. Liver biopsies via peritoneoscopy to eradicative radiotherapy while only 21 % 10. Laparotomy with extensive tissue sampling had documented disseminated (Stage IV) disease. Bipedal lymphography served to and Medicine Branches of the National Cancer increase the number of patients with Institute since January 1971. Staging evaluation employed the diagnostic tests described in Table I, the sequence of studies TABLE IV.-Sequential Diagnostic Staging being interrupted when disseminated extraResults for 100 Consecutive Cases of nodal involvement was histologically conUntreated Lymphoma firmed. The age and sex distributions and Ann Arbor staging (%) the histopathological classification relative to primary site of involvement are given in III IV I II Tables II and III. The projected evaluation Usual tests 21 42 8 29 Lymphography

TABLE II.-Age and Sex Distributions for 100 Consecutive Untreated Cases of Lymphoma

Bone marrow Liver biopsy

Laparotomy

4 4 3 2

18 16 15 11

57 39 28 23

21 41 54 64

Age at diagnosis

recognizable lymphatic involvement on a more generalized basis (Stage III). Closed bone marrow biopsy defined unequivocal tumour infiltration in a further 20% of was incomplete in 11 of the first 100 patients patients not already appreciated to have for the following reasons: poor medical Stage IV involvement (or a leukaemic condition (4), incomplete laparotomy elseof their lymphoma). Liver needle where (2), marked thrombocytopenia (1), and phase biopsy (either percutaneous or via perifor poorly documented reasons (4). toneoscopy) documented hepatic involvement with rewarding frequency as reported RESULTS by Chabner et al. ( 1975) at this Symposium. Sequential staging Laparotomy with wedge liver biopsy The usual clinical studies referred to in further detected additional unsuspected Males/females 50/50

1-20 5

27-40 18

41-60 59

61-80 18

TABLE III.-Histological Classificationsfor 100 Consecutive Untreated Cases of Lymphoma Primary,

site Nodal

Histology* STEM

DH

DM

3 2

15

3

DLPD 11

DLWD 6

NLPD 30

NM 13

Extranodal 7 7 1 Unknown 1 1 * DH = diffuse histiocytic, DM = diffuse lymphocytic and histiocytic (mixed), DLPD = diffuse poorly differentiated lymphocytic, DLWD = diffuse well differentiated lymphocytic. NLPD nodular poorly differentiated lymphocytic, NM = nodular lymphocytic and histiocytic (mixed).

PATTERNS OF INVOLVEMENT WITH MALIGNANT LYMPHOMA

involvement and nearly two-thirds of the series eventually had documented extranodal dissemination. Conversely, only 13% remained after completion of staging with the type of local-regional disease which could even be considered for conventional radiotherapy techniques. The 23 patients with Stage III involvement deserve special comment. Although seemingly having disease confined to lymph nodes, 14 of these 23 had biopsy proven involvement of nodes located in the free mesentery and/or porta hepatis (10/14 cases were examined) or in the epitroclear/popliteal regions. Thus, only 9 of the 23 had a distribution of lymphatic disease as usually observed in Hodgkin's disease. Generally speaking, the pattern of involvement for Stage III cases did not lend itself to the concept of eradicative radiotherapy using " total nodal irradiation" as this phrase was defined by Johnson (1969). More extensive lymphatic irradiation to encompass the mesenteric region, Waldeyers ring, etc., might be considered but is rather unattractive in view of the high frequency with which extranodal involvement can be demonstrated by random biopsy procedures. It is much more probable that very few surgical Stage III patients in fact have disease truly confined to lymph nodes.

Clinical observations Prospective staging has yielded considerable information with respect to the anatomical distribution of disease but the reliability for guiding therapeutic decisions requires verification. In other words, is staging of sufficient accuracy to guide the selection of treatment? The answer to this question then relates to how often " false negatives " occur when widespread dissemination cannot be documented in those patients with apparently localized presentations. One illustration relevant to this matter concerns cases with lymph node presentations having a diffuse histological type of lymphocytic lymphoma. The prospective staging study included 17 such patients (Table V), 16 of whom had extranodal involvement detected by comprehensive evaluation although approximately half of these cases presented with more clinically limited disease. In the solitary case with localized (Stage II with poorly differentiated diffuse lymphocytic histology) involvement after completion of staging, intensive regional irradiation was followed shortly by the appearance of extranodal dissemination. Thus, all patients with diffuse lymphocytic lymphoma were biologically Stage IV but staging was falsely negative in one case.

TABLE V.-Correlating of Final Staging with Primary Site and Histology for 100 Consecutive Untreated Cases Ann Arbor staging

Primary site Nodal

Histology DLPD DLWD DM DH STEM NLPD NM

I

II

III

IV 10

0

I

0

0

0

0

0

0

1

0

3

6

0

0

1

0

0

2

1 10 4

Extranodal DLPD DH STEM

1

2 3

0

0

0

0

1 0

Undetermined DH NLPD NM

6 2 6 2 19 7

5 2 2

0

0

0

0

0

0

1 1

0

0

0

1

Definitions

239

as

for Table III.

240

R. E. JOHNSON ET AL.

al. (1971), Vinciguerra and Silver (1973), and Jones, Rosenberg and Kaplan (1972) have described the diagnostic results of rigorous staging in the malignant lymphomata. The temptation now facing clinicians will be a tendency to accept the results of staging at face value rather than within the overall framework of past clinical experience. To succumb to this temptation will only result in patients being given extensive lymphatic irradiation for neoplasms which are seldom amenable to control with such treatment in contrast to Hodgkin's disease. Further, there is a deserving emphasis needed on the distinctions between malignant lymphomata originating in lymph nodes compared with those primary in extranodal sites. An impressive literature bears witness to the merit of this distinction and indicates that primary extranodal lymphomata, while frequently localized, often resemble carcinomata in their propensity for extension both haematogenously and to regional lymph nodes. Malignant lymphomata primary in Waldeyer's ring should be included in the extranodal category despite these sites having some nodal characteristics. To include, and thereby confuse, Waldeyer ring lymphomata with peripheral lymph node presentations not only qualifies one as a " lumper " rather than a " splitter " but also suggests clinical naiveity with respect to understanding the behaviour of these diseases. In summary, several requirements are obvious for the future. The first is the need to expose the fallacy of reliance upon staging for treatment decisions while disregarding other cinicohistological factors of at least equal if not greater biologically prognostic significance. Secondly, more effective systemic treatment must be developed and then utilized in a greater proportion of patients, as discussed. Finally, confusions related to DISCUSSION histopathological classification must be A number of recent reports, including resolved and a more appropriate anatomithose of Ferguson et al. (1973); Hanks et cal staging system universally adopted. al. (1972), Hass et al. (1971), Veronesi et We do not agree with the conclusion of It is this type of biological appraisal of staging reliability which must be extended to various surgical stages and histological subtypes in all series so studied. The present series has a maximum observation time of only 30 months and therefore does not permit critical interpretation of each risk category. Nonetheless, the preliminary observations clearly coincide with our previous clinical experience and suggest several conclusions may be tentatively drawn with a reasonable degree of confidence, namely: (1) lymph node presentations confined to a single group of nodes are often seemingly controlled with localized irradiation alone. In contrast, involvement of 2 or more lymphatic areas is indicative of biological dissemination and requires systemic therapy; (2) primary extranodal lymphomata merit " tumoricidal " radiotherapy when confined to the primary site and such treatment is definitive in a significant proportion, as reviewed by Freeman, Berg and Cutler (1972). Extension of disease to regional nodes at diagnosis sharply reduces, but does not eliminate, the control rate with regional radiotherapy whereas more distant lymphatic involvement should be interpreted as indicative of even more diffuse dissemination; (3) a vast majority of newly diagnosed patients with malignant lymphoma present with anatomically generalized disease except in centres with highly selected referral patterns. Consequently, progress in therapeutics will necessitate development of more effective systemic treatment and the more routine application of systemic therapy, not only for cases with obviously generalized disease but additionally for cases with a significant probability of biologically generalized involvement despite " early " staging.

PATTERNS OF INVOLVEMENT WITH MALIGNANT LYMPHOMA

Jones et al. (1973) that the Ann Arbor staging classification is a satisfactory " guide to the management and prognosis of the non-Hodgkin's lymphomas ". The contrary would seem more realistic to us, namely that an alternate staging schema incorporating both histological and clinical (e.g., primary site of involvement) determinants relevant to biological behaviour is not only warranted but imperative. REFERENCES CHABNER, B., JOHNSON, R., CHRETIEN, P., SCHEIN,

P., YouNG, R., CANELLOS, G., HUBBARD, S. & DEVITA, V. (1975) Percutaneous Liver Biopsy, Peritoneoscopy, and Laparotomy. An Assessment of Relative Merits in the Lymphomata. Br. J. Cancer, 31, Suppl. II, 242. FERGUSON, D., ALLEN, L., GRIEM, M., MORAN, M.,

RAPPAPORT, H. & ULTMANN, J. (1973) Surgical Experience with Staging Laparotomy in 125 Patients with Lymphoma. Arch8 intern. Med, 131, 356.

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FREEMAN, C., BERG, J. & CUTLER, S. (1972) Occurrence and Prognosis of Extranodal Lymphomas. Cancer, N. Y., 29, 252. HANKS, G., TERRY, L., BRYAN, J. & NEWSOME, J. (1972) Contribution of Diagnostic Laparotomy to Staging Non-Hodgkin's Lymphoma. Cancer, N. Y., 29, 41. HASS, A., BRUNK, S., GULESSERIAN, H. & GIVLER, R. (1971) The Value of Exploratory Laparotomy in Malignant Lymphoma. Radiology, 101, 157. JOHNSON, R. (1969) Modern Approaches to the Radiotherapy of Lymphoma. Semin Hemat., 6, 357. JONES, S., FUKS, Z., BULL, M., KADIN, M., DORMAN, R., KAPLAN, H. ROSENBERG, S. & KIM, H. (1973) Non-Hodgkin's Lymphomas. IV. Clinicopathologic Correlation in 405 Cases. Cancer, N.Y., 31, 806. JONES, S., ROSENBERG, S. & KAPLAN, H. (1972) Non-Hodgkin's Lymphomas. I. Bone Marrow Involvement. Cancer, N. Y., 29, 954. VERoNESI, U., BONADONNA, G., MUSUMEcI, R., PIZZETTI, F., GENNARI, L., BERETTA, G. & DELENA, M. (1971) Indications and Preliminary Results of Diagnostic Laparotomy in Malignant Lymphomas. Tumori, 57, 425. VINCIGUERRA, V. & SILVER, R. (1973) The Importance of Bone Marrow Biopsy in the staging of Patients with Lymphosarcoma. Blood, 41, 913.