Reproducibility in Morphologic Classification of Non

Reproducibility in Morphologic Classification of Non-Hodgkin's Lymphomas Using the Lukes-Collins System The Southeastern Cancer Study Group Experience CLARENCE C. WHITCOMB, M.D., JOHN D. CRISSMAN, M.D., ANDREW FLINT, M.D., JOHN B. COUSAR, M.D., ROBERT D. COLLINS, M.D., AND GERALD E. BYRNE, JR., M.D.

MORPHOLOGIC CLASSIFICATION of non-Hodgkin's lymphomas (NHL) involves detailed observations of nuclear and cytoplasmic features in sections of neoplastic tissue. The classification system developed by Lukes and Collins8,9 integrates immunologic attributes of the neoplastic cells with histopathologic features. While some of the types of NHL defined within this system may be identified by histopathologic features in tissue sections, morphologic observations alone may not be sufficient for reliable diagnosis of all of the types. Critical morphologic features may not always be revealed clearly in routinely prepared tissue sections, and observed features may not be interpreted reproducibly.

Hematopathology Subcommittee of the Southeastern Cancer Study Group and the Departments of Pathology, University of Miami School of Medicine, Miami, Florida; Wayne State University, Detroit, Michigan; University of Michigan, Ann Arbor, Michigan; and Vanderbilt University, Nashville, Tennessee

The study reported here was undertaken to evaluate to what extent five pathologists, using routinely prepared histologic sections, could reproducibly recognize histopathologic entities defined by morphologic criteria specified within the Lukes-Collins system. Concordance among the pathologists with respect to these morphologic entities was determined, and specific types of disagreements were identified. In addition, to assess whether or not disagreements could be reduced as the pathologists accumulated experience with the classification system, selected cases were classified independently on two occasions. The findings of these analyses are reported here. Methods

Histologic sections of diagnostic biopsy specimens were available for 249 patients with NHL. The patients had been followed in clinical studies of the Southeastern Cancer Study Group (SECSG). The histologic slides were obtained from Dr. Ronald Dorfman, who had served as pathology reviewer for the SECSG, or from the Repository Center for Lymphoma Clinical Studies.3 Varying numbers of sections were available in each case. Most had been prepared from formalin-fixed, paraffin-embedded tissue and had been stained only with hematoxylin and eosiri. Blocks were not available for preparation of additional histologic sections. Received December 22, 1983; received revised manuscript and acThe cases had been classified previously using the Rapcepted for publication March 13, 1984. paport classification system14 as poorly differentiated Supported in part by Grants CA-19657 and CA-18055 from the Nalymphocytic lymphoma (61 cases), mixed lymphocytictional Cancer Institute, National Institutes of Health, Department of Health and Human Services. histiocytic lymphoma (51 cases), or histiocytic lymphoma Address reprint requests to Dr. Byrne: Department of Pathology (D(134 cases). In the majority of the cases, the growth pattern 34) University of Miami School of Medicine, P.O. Box 016960, Miami, of the neoplastic cells was diffuse. In 26 of the cases of Florida 33101.

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Five pathologists of the Southeastern Cancer Study Group reviewed routinely prepared histologic sections from 249 cases of non-Hodgkin's lymphoma. They classified these cases morphologically, using criteria of the Lukes-Collins classification system. To evaluate reproducibility in classification, the individual interpretations of each pathologist were compared with a consensus interpretation. The pathologists recognized general morphologic features of follicular center cell lymphomas in 87-94% of such cases, but they identified specific morphologic types much less consistently. Significant differences of interpretation were encountered with respect to small cleaved follicular center cell, large cleaved follicular center cell, and large transformed (large noncleaved) follicular center cell types. Inadequacies of routine histologic sections contributed substantially to these disagreements. Ancillary immunologic technics may be required to improve consistency in recognition of some morphologic types, as well as to characterize cases that are not classified easily by morphology alone. (Key words: Lymphoma; Classification; Reproducibility; Histopathology; Morphology; Problems) Am J Clin Pathol 1984; 82: 383-388

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poorly differentiated lymphocytic type, 43 cases of mixed type, and 16 cases of histiocytic type, however, the growth pattern was either nodular or nodular and diffuse within adjoining areas of neoplastic tissue. The five pathologists (GEB, RDC, JBC, JDC, and AF), all members of the SECSG Hematopathology Subcommittee, reviewed histopathologic features of the various types of NHL defined within the Lukes-Collins classification2'8,9 before examining any of the tissue sections. They then independently and without knowledge of any clinical data examined all available slides and attempted to classify each case within some category of the Lukes-Collins classification. When a case could not be assigned definitely to a specific category, explanatory and descriptive comments were recorded.

Each pathologist's interpretation of each case was compared with the consensus classification. Possible pairings of interpretations by the pathologist and the consensus were tabulated in N X N contingency tables. Various interpretations were compared in different analyses. For simple analyses (N = 2) interpretations such as "case classified as X" and "case not classified as X" were used. For more detailed analyses, each of the N categories of the contingency table corresponded to one or more specific morphologic types of NHL. The N categories were mutually exclusive and encompassed the entire range of morphologic entities encountered. Various tabulations of individual and consensus interpretations were inspected for disagreements that might indicate particular biases. In 2 X 2 tabulations, McNemar's test was used to assess the significance of discordant interpretations." A more generalized form of this test applicable to larger contingency tables12 was used to evaluate the disagreements revealed in more detailed analyses. Sixty cases were selected from among the cases in which a consensus was reached only during joint review and discussion. These 60 cases included all of the morphologic types in approximately the same frequencies as they were encountered in the original study population. The pa-

thologists reexamined these cases and rendered a second classification opinion, without reference to their original interpretations, from one to five months after the meetings, during which the cases had been discussed. The initial and subsequent interpretations of these 60 cases were compared with the consensus classification and with each other as described above. Results Of the 249 cases reviewed, 44 (18%) ultimately were excluded because the quality of the histologic sections was judged to be inadequate for proper assessment of cytologic details required for classification using the criteria of the Lukes-Collins system. The 205 cases of acceptable technical quality were classified by consensus as follows: small cleaved follicular center cell lymphoma (SCFCCL)—51 cases; large cleaved follicular cell lymphoma (LCFCCL)—27 cases; large transformed (large noncleaved) follicular center cell lymphoma (LTFCCL)— 64 cases; immunoblastic sarcoma of B lymphocytes (IBSB)—6 cases; node-based T-cell lymphoma (NBTCL)—5 cases; lymphoma of small transformed (small noncleaved) cells (STCL)—5 cases; convoluted lymphocytic lymphoma (CONVLL)—7 cases; and small lymphocytic lymphoma (SLL)—6 cases. The remaining 34 cases were classified as indeterminate. Of the indeterminate cases, 18 were described as having some features similar to those of the LCFCCL or LTFCCL categories, but they could not be assigned definitively to either of those categories. For the other 16 indeterminate cases, no consensus could be established with regard to any of the defined categories. In all of these cases, small lymphoid cells predominated. The cases had been classified previously using the Rappaport system as either diffuse poorly differentiated lymphocytic or diffuse mixed lymphocytic-histiocytic lymphoma. Because the neoplastic cells of the SCFCLL, LCFCCL, and LTFCCL types of NHL have morphologic and immunologic features similar to the cells of normal lymphoid follicles910 and because the clinical responses of these types to current therapies appear to be more favorable than the responses of the IBSB, NBTCL, STCL, or CONVLL types, 1315 - 1719 ' 21 the 142 cases classified in this study as SCFCCL, LCFCCL, or LTFCCL were grouped together in some analyses. These three types are designated collectively Group 1. Because of their potentially more aggressive nature, cases classified as IBSB, NBTCL, STCL, or CONVLL also were grouped together and collectively are designated Group 2. . The distribution of the 205 cases among the categories outlined above is shown in Table 1. Also indicated are the numbers of cases of each type in which three, four, or all five of the reviewers concurred during their initial


A final (consensus) classification of each case was established if at least four of the five pathologists agreed in their independent interpretations. This strict requirement was made in order to insure that when the interpretation of any one pathologist was omitted, the majority opinion would remain unchanged. Cases for which such a consensus was not achieved during the independent evaluations were reviewed subsequently by all five pathologists using a multiheaded microscope, and a consensus was derived by discussion. Cases were excluded from the studies if at least three of the five reviewers stated during their independent examinations that the histologic sections were technically inadequate for evaluation, or if a similar judgment was made during the joint review sessions.

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Table 1. Distribution of Cases among the Morphologic Categories Encountered in the Study*

Category SCFCCL LCFCCL LTFCCL IBSB NBTCL STCL CONVLL SLL

No. Cases

n=3

n=4

n= 5

51 27 64 6 5 5 7 6

10 4 13 1 3 1 2 3

6 13 16 1 0 0 1 0

16 5 6 0 0 0 1 0

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Table 2. Ranges of Two Concordance Measures— Expressed as Percentages—Calculated for the Five Pathologists with Respect to Morphologic Categories as Indicated Category

Concordance Measure A

Concordance Measure B

SCFCCL LCFCCL LTFCCL

63-76% 51-85% 36-80%

68-93% 31-58% 49-90%

Measure A = proportion of cases classified as indicated by consensus that were classified similarly by individual. Measure B = proportion of cases classified as indicated by individual that were classified similarly by consensus.


* See text for explanation of abbreviations. Also shown are the numbers of cases in each category in which 3, 4. or all 5 of the pathologists concurred during their initial independent evaluations. egory including all other types revealed significant differences between the classifications of each pathologist independent reviews. In only 32% of the 205 cases did and the consensus (P < 0.001 to P < 0.01). For three of either four or all five reviewers agree during the initial the pathologists the differences were due primarily to disreviews. For the other cases, among which were almost agreements between the categories LCFCCL and all of the cases ultimately classified as IBSB, NBTCL, LTFCCL. These individuals all exhibited a bias toward and STCL, a consensus was established only after joint classifying as LCFCCL cases that were assigned to the review and discussion. LTFCCL category by consensus. A fourth individual exhibited the opposite bias, classifying as LTFCCL cases Overall agreement with consensus was determined for that were assigned to the LCFCCL category by consensus. each pathologist by dividing the number of cases in which the pathologist's interpretation was in agreement with the Two pathologists tended to classify cases of SCFCCL consensus by the total number of cases classified. Agreeas either LCFCCL or LTFCCL. The presence of a nodular ments with respect to specific categories were evaluated growth pattern appeared to aggravate these tendencies. for each pathologist by calculating: A—the proportion of When cases in which a nodular growth pattern, or in cases assigned to the specific category by consensus that which both nodular and diffuse areas were present, were were classified similarly by the pathologist, and B—the excluded from analysis, these two reviewers committed proportion of cases assigned to the category by the pafar fewer misclassifications of this type. thologist that were classified similarly by consensus. The interpretations of the individual pathologists also Overall agreement with consensus ranged from 49% were compared with the consensus with respect to asto 60% for the five pathologists in the study. Ranges of signments of cases to Group 1—on the basis of classifithe two measures of concordance—A and B described cation as SCFCCL, LCFCCL, or LTFCCL, or to Group above—between individual pathologists and the consen2—on the basis of classification as IBSB, NBTCL, STCL, sus, with respect to the categories SCFCCL, LCFCCL, or CONVLL. Table 4 shows the ranges of the proportions and LTFCCL, are shown in Table 2. The ranges represent of cases within Group 1 and Group 2 that, using an the least and greatest values observed among the five individual's interpretation, could be assigned to Group pathologists with respect to the stated category. Proportions A and B for IBSB, NBTCL, STCL, CONVLL, and Table 3. Representative 4 X 4 Tabulation (Contingency SLL are not shown because of the small numbers of cases Table) Comparing the Classifications of One of the Pain each of these categories. Differences between these two thologists with the Consensus with Respect to the Catcorrelated proportions were evaluated by McNemar's test. egories Indicated. The "Other" Category Includes Cases With respect to the categories LCFCCL and LTFCCL, of IBSB, NBTCL, STCL, CONVLL, and SLL, as well as the Chi-square statistic was significant (P < 0.01) for three Indeterminate Cases in this Tabulation of the five pathologists, indicating a nonrandom tendency for either false-negative or false-positive interpretations Classified by Pathologist as: by the pathologist vis a vis the consensus. Consensus SCFCCL LCFCCL LTFCCL Other More specific patterns of disagreement between indiClassification vidual pathologists and consensus were revealed in larger SCFCCL 32 18 0 1 contingency tables, such as illustrated in Table 3. Analyses LCFCCL 0 25 1 I LTFCCL 1 20 36 7 of tabulations comparing the categories SCFCCL, Other 8 14 38 3 LCFCCL, LTFCCL, and, for completeness, a general cat-

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Table 4. Ranges of the Proportions of Cases within Group 1 and Group 2 that, Using Interpretations of Each Pathologist, Would Be Assigned to the Same or to a Different Group Percent Assigned by Individuals to: Assigned by Consensus to:

Group 1

Group 2

Not Assignable

Group 1 Group 2

87-94 13-35

2-5 39-78

2-10 9-30

For the 60 cases that were examined independently on two different occasions, before and after meetings during which they were reviewed and discussed, the initial and postreview interpretations of each pathologist were compared. These interpretations also were compared with the consensus established during the meetings. The most revealing of these analyses compared classifications among the four categories SCFCCL, LCFCCL, LTFCCL, and "all other morphologic types." Disagreements in classification of cases between the categories LCFCCL and LTFCCL accounted for a major proportion of the differences between the initial and postreview interpretations for three pathologists. For two of these pathologists, the differences between their postreview interpretations and the consensus were much less than the differences between their initial interpretations and consensus.*

* In most of the analyses involving only 60 cases, Cochran's criteria for minimal expected entries were not fulfilled. Although such strict requirements on expected entries may not be necessary for large contingency tables," secure interpretations of significance for the test statistics were not considered possible in these analyses.

Discussion The five pathologists agreed with a consensus in 4 9 60% of 205 cases of NHL classified using only morphologic criteria of the Lukes-Collins system. In only 32% of the cases, however, was the consensus—representing agreement by at least four of the five pathologists—established during the initial independent examinations of the histologic material. For those cases in which no consensus was established during these independent reviews, agreement among the five pathologists was reached by examination and discussion of slides using a multiheaded microscope. The majority of the cases (142 of 205) ultimately were classified by consensus as small cleaved follicular center cell lymphoma (SCFCCL)—51 cases, large cleaved follicular center cell lymphoma (LCFCCL)—27 cases, or large transformed (noncleaved) follicular center cell lymphoma (LTFCCL)—64 cases. The proportions of cases in which the five pathologists agreed with the consensus with respect to the categories LCFCCL and LTFCCL varied greatly (Table 2). Disagreements arose from differing perceptions of large cleaved and large transformed cells. A strong bias for misclassifying cases of LTFCCL as LCFCCL was exhibited by three of the pathologists. Histologic imperfections unquestionably contributed substantially to these disagreements. Almost all of the histologic sections reviewed in these studies were prepared from formalin-fixed, paraffin-embedded tissue. Cytologic details are visualized more clearly when fixatives such as B-5 or Zenker's solutions are used. In addition, sections stained with periodic acid-Schiff or methyl green pyronine were available in only a few cases. The latter stain is particularly helpful in enhancing the features of transformed lymphoid cells as found in large transformed (noncleaved) follicular center cell lymphoma and small transformed (noncleaved) cell lymphoma. Limitations of the routinely prepared histologic sections reviewed in this study are highlighted by the large number of cases (44 of 249) that ultimately were excluded because the technical quality was judged to be inadequate for evaluation of cytologic features required for classification using the criteria of the Lukes-Collins system. When the pathologists reexamined a sample of 60 cases after attending meetings during which initial disagreements were discussed and a consensus was established, biases for classifying cases of LTFCCL as LCFCCL were much less than during the initial evaluations. This suggests that consistency in discrimination of these two morphologic types may improve with the accumulation of experience. However, disagreement between these two types was not eliminated completely. Difficulties in determining a "predominant" cell when different cytologic types of neoplastic cells were admixed


1, to Group 2, or, because no specific classification had been made by the pathologist, could not be assigned to either. Both the magnitudes and ranges of the proportions summarized in Tables 2 and 4 are of interest. There was considerable variability among the pathologists in the proportions of cases in which they agreed with the consensus (concordance measure A) with respect to specific morphologic categories. For example, the proportions of cases of LTFCCL that were classified correctly by the individual pathologists varied from 36% to 80% (Table 2). With respect to assignments of cases to Group 1, however, their agreement with consensus was higher and less variable. The proportions of cases within Group 1 that, using an individual's classification, could be assigned to Group 1, irrespective of agreement with respect to specific categories, varied from 87% to 94% (Table 4). Agreement with respect to assignment of cases to Group 2, irrespective of specific classification, was lower and varied from 39% to 78% (Table 4).

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can be analyzed to some extent. Lymphomas of types IBSB, NBTCL, STCL, and CONVLL (types included within Group 2) appear to be more aggressive than the FCC lymphomas (included in Group 1). The pathologists in this study individually misclassified from 13% to 35% of the cases within Group 2 as FCC lymphoma—most frequently interpreting the cases as LTFCCL. While excellent histologic tissue sections might enhance distinctive morphologic features of the entities in Group 2, thereby improving recognition of these types, ancillary technics to demonstrate T-cell membrane properties or intracytoplasmic immunoglobulin may be very helpful for differentiating NBTCL and IBSB from the FCC lymphomas. Classification of one type of FCC lymphoma as a different type of FCC lymphoma may have less serious implications with respect to clinical management. Differences in survival between LCFCCL and LTFCCL, for example, have not been great in retrospective studies completed to date.1517,19,21 However, classification of cases of SCFCCL in which a nodular growth pattern is prominent as LCFCCL or LTFCCL, a bias exhibited by two of the pathologists in this study, might result in the selection of therapy more aggressive than appropriate. Problems in discriminating large cleaved from large transformed cells in the material available or difficulties in establishing a predominant cell type contributed substantially to the ultimate decisions to classify some cases as indeterminate. In 12 of the 18 cases of large cell lymphoma so classified, the pathologists clearly recognized some features consistent with lymphomas of FCC type. In these cases, however, cleaved and transformed cells were admixed in varying proportions from area to area, such that a predominant cell type could not be identified clearly. Criteria within the Lukes-Collins system do not provide clear rules for assigning such cases to the specific categories LCFCCL or LTFCCL. The finding of 16 cases of diffuse small cell lymphoma that could not be classified as either SLL or SCFCCL also is noteworthy. Such cases may represent variants of FCC lymphomas, or they may be distinct entities that have not yet been characterized fully. Lymphomas designated as intermediate lymphocytic lymphoma 10,20 or as centrocyte lymphoma 18 may be included among such cases. It also is possible that some may represent T-cell lymphomas. 6 The clinical significance of such small cell lymphomas of indeterminate type is not known. Consistency of histopathologic classification of NHL can be improved considerably by improving the quality of histologic sections. Special care in tissue handling, fixation, processing, and staining are necessary to this end. Fixatives such as B-5 are superior to formalin for enhancing cytologic details. Stains such as periodic acidSchiff and methyl green pyronine should be used liberally. While it is likely that many of the types of NHL defined


also contributed to disagreements with respect to cases in Group 1 (SCFCCL, LCFCCL, and LTFCCL). It is noteworthy that such difficulties were more pronounced for two pathologists in cases in which a distinct nodular growth pattern was present. Such difficulties are resolved in other classification systems, such as the Rappaport system,14 by admitting a "mixed" category for cases in which different cytologic types are admixed. No such category is used within the Lukes-Collins classification, however, even though admixtures of cells are acknowledged.8 The types of NHL included in Group 1 (SCFCCL, LCFCCL, and LTFCCL) are characterized morphologically by the presence of follicular nodules of neoplastic cells or by the presence of cleaved cells resembling the cleaved lymphocytes of normal follicles. These three types of NHL collectively are referred to as follicular center cell (FCC) lymphomas. Using the features of nodularity and/or cleaved cells to identify FCC lymphomas without specifying a precise type (SCFCCL, LCFCCL, or LTFCCL), the five pathologists independently agreed with the consensus in 87-94% of the 142 cases in Group 1. Stated conversely, the pathologists classified FCC lymphomas as some "other" morphologic type in only 613% of cases. Recognition of general morphologic features of FCC lymphomas appears to be reasonably reproducible. Recognition of nodularity in tissue sections of NHL has been shown to be quite reproducible.'•4-5,7 Recognition of neoplastic nodules within FCC lymphomas could account for the high levels of reproducibility in identifying the cases in Group 1. Distinct nodularity, however, sufficient to have engendered recording of the growth pattern as nodular or as nodular and diffuse, was present in only 45% of the cases in Group 1. Apparently, other morphologic features of FCC lymphomas also can be recognized quite reproducibly. The presence of small cleaved cells would appear to be a distinctive morphologic feature in FCC lymphomas with a diffuse growth pattern. Cases not identified as FCC lymphomas were classified as IBSB (6 cases), NBTCL (5 cases), STCL (5 cases), CONVLL (7 cases), SLL (6 cases), or were designated as indeterminate (34 cases). Because of the small number of cases in these specific categories, concordance statistics for specific types are not very meaningful. It is noteworthy, however, that for many of the cases ultimately classified in Group 2, (IBSB, NBTCL, STCL, and CONVLL) a consensus was established only after joint review and discussion by the five pathologists. Distinctive "diagnostic" features were not perceived by a majority of the pathologists during their initial independent reviews. Indeed, many of the cases of IBSB, NBTCL, and STCL were classified as large cell FCC lymphomas, i.e., as LCFCCL or LTFCCL. Clinical consequences of disagreements in classification

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within the Lukes-Collins classifications can be recognized by morphologic features alone—given excellent histologic material—ancillary studies may be required in some cases. Immunologic phenotyping can be of particular importance in cases in which morphologic features of FCC lymphomas are not apparent. Such technics will improve the recognition of IBSB and NBTCL, and they should be of value in more definitively characterizing cases, especially those comprised of small cells, for which distinct nosologic categories are not yet clearly defined.


7. Kim H, Zelman RJ, Fox MA, et al: Pathology Panel for lymphoma Clinical Studies: A comprehensive analysis of cases accumulated since its inception. J Natl Cancer Inst 1982; 68:43-67 8. Lukes RJ, Collins RD: New approaches to the classification of the lymphomata. Br J Cancer 1975; 31(Suppl 2): 1-28 9. Lukes RJ, Parker JW, Taylor CR, Tindle BH, Cramer AD, Lincoln TL: Immunologic approach to non-Hodgkin's lymphomas and related leukemias. Analysis of the results of multiparameter studies of 425 cases. Semin Hematol 1978; 15:322-351 10. Mann RB, Jaffe ES, Berard CW: Malignant lymphomas—a conceptual understanding of morphologic diversity. Am J Pathol 1979;94:105-192 11. Maxwell AE: Analysing qualitative data. London, Methucan and Co, 1961, p 163 Acknowledgments. The authors specifically thank the following in- 12. Maxwell AE: Comparing the classification of subjects by two independent judges. J Psychiatry 1970; 116:651-655 dividuals: Dr. Ronald Dorfman, Stanford University, and Drs. Henry Rappaport and Bharat Nathwani, City of Hope Medical Center, Duarte, 13. Nathwani BN, Kim H, Rappaport H: Malignant lymphoma, lymphoblastic. Cancer 1976; 38:964-983 California, who provided histologic slides for these studies; Drs. John 14. Rappaport H: Tumors of the hematopoietic system, Atlas of tumor Durant and Richard Gams, University of Alabama, who provided adpathology, section 3, fascicle 9. Washington, D.C., Armed Forces ministrative support; Mr. Tim Aldrich, University of Miami, who conInstitute of Pathology, 1966, pp 97-161 tributed to the design of the study; and Ms. Kimberly Eskandari and 15. Rosenberg SA, Berard CW, Brown BW, et al: National Cancer Mrs. Maria Fiol, who provided technical assistance. Institute sponsored study of classifications of non-Hodgkin's lymphoma. Summary and description of a working formulation for clinical usage. Cancer 1982; 49:2112-2135 References 16. Stein RS, Cousar JB, Flexner JM, et al: Malignant lymphomas of 1. Byrne GE: Rappaport classification of non-Hodgkin's lymphoma. follicular center cell origin in man: III Prognostic features. Cancer Histologic features and clinical significance. Cancer Treat Rep 1979; 44:2236-2243 1977;61:935-944 17. Strauchen J A, Young RC, DeVita VT, Anderson T, Fantone JC, 2. Collins RD, Leech JH, Waldron JA, Flexner JM, Glick AD: DiBerard CW: Clinical relevance of the histopathological subclasagnosis of hematopoietic, mononuclear, and lymphoid cell neosification of difFuse "histiocytic" lymphoma. N Engl J Med 1978; plasms, Manual of clinical immunology. Edited by NR Rose, 299:1382-1387 H Friedman. Washington, D.C., American Society for Micro18. Toldsdorf G, Stein H, Lennert K: Morphologic and immunologic biology, 1976, pp 718-732 definition of a malignant lymphoma derived from germinal3. DeVita VT, Rappaport H, Frei E: Announcement of formation of: center cells with cleaved nuclei (centrocytes). Br J Cancer 1980; The Lymphoma Task Force and Pathology Reference Center. 41:168-182 Cancer 1968;22:1087-1088 19. Warnke RA, Strauchen JA, Burke JS, Hoppe RT, Campbell BA, 4. Ezdinly EZ, Costello W, Wassner LP, et al: Eastern Cooperative Dorfman RF: Morphologic types of diffuse large-cell lymphoma. Group experience with the Rappaport classification of nonCancer 1982; 50:690-695 Hodgkin's lymphomas. Cancer 1979; 43:544-550 20. Weisenberger DD, Nathwani BN, Diamong LW, Winberg CD, 5. Jones SE, Butler JJ, Byrne GE, Coltman CA, Moon TE: HistoRappaport H: Malignant lymphoma, intermediate lymphocytic pathologic review of lymphoma cases from the Southwest Ontype. Cancer 1981; 48:1415-1425 cology Group. Cancer 1977; 39:1071-1076 21. Whitcomb CC, Cousar JB, Flint A, et al: Subcategories of histiocytic 6. Kikuchi M, Mitsui T, Matsui N, et al: T-cell malignancies in adults: lymphoma: Associations with survival and reproducibility of Histopathologic studies of lymph nodes in 110 patients. Jpn J classification. The Southeastern Cancer Study Group experience. Clin Oncol 1979; 9(Suppl):407-422 Cancer 1981; 48:2464-2474