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ICANCER RESEARCH 26 Part 1, 1063-1081,June 1966] The Pathology and Nomenclature of Hodgkin's Disease ROBERT J. LUKES AND JAMES J. BUTLER Department of Pathology, University of Southern California, School of Medicine, Los Angeles, California (R. J. L.) and Department of Pathology, M. D. Anderson Hospital, Houston, Texas (J. J. B.) Summary The diverse morphologic expressions of Hodgkin's disease have been reviewed and compared to the numerous histologie terms in the literature and the author's recently proposed histologie types. The relationship of the histologie findings to the clinical stages and survival has also been analyzed. The histologie ex pressions of the Hodgkin's disease process appear to be reparable into the following 6 groups: (a) lymphocytic and/or histiocytic (L & H),1 nodular; (b) lymphocytic and/or histiocytic (L & H), diffuse; (c) nodular sclerosis; (d) mixed; (e) diffuse fibrosis; and (/) reticular. The L & H types represent essentially a pre dominant lymphocytic proliferation with histiocytes, while diffuse fibrosis and reticular are associated with lymphocytic depletion. Nodular sclerosis has a remarkably high incidence of mediastinal involvement when initially observed, exceeding all other types combined, and appears to represent a regional expression of Hodgkin's disease in the mediastinum. The mixed type appears to reflect a changing disease state. These histologie types, with the exception of nodular sclerosis, represent differ ences in the frequency of lymphocytes and Reed-Sternberg cells and serve to emphasize their inverse relationship. The histologie findings are regarded as reflections of differences in the state of the host responsiveness and are believed to be related to the recently described immunologie defect. The demonstrated relationship between these histologie types, and the clinical stages and survival, provides further support for the importance of host factors and also presents an effective basis for prog nostication. In addition a new histologie type, nodular sclerosis, has emerged as the most important prognostic type when observed in clinical Stage I. The majority of the terms proposed in the literature for the histologie types of Hodgkin's disease represent designations for the lesion with a predominantly lymphocytic proliferation of either nodular or diffuse type. This lesion is of prognostic signifi cance, but it includes only a small proportion of the prolonged survivors. The classical histologie types of Jackson and Parker are of limited effectiveness in prognosis since the heterogeneous granuloma group includes 80-90% of reported series, contains 79% of the survivors at 15 years in our study, and yet has a relatively short median survival in our comparison study. Introduction The unique diversity of the morphologic features in Hodgkin's disease and the variable rates of progression of the disease have evoked an almost unparalleled variety of terms in an attempt to 1The groups designated lymphocytic and/or histiocytic will be referred to as "L & H" hereafter with the modification of the nodular or diffuse type. relate the histologie features to survival and to depict the as yet unsettled nature of the basic process. Over SO terms for the disease were collected from the literature by Wallhauser (35) from the 1st century after Thomas Hodgkin's description. This profusion of names for the disease primarily reflects the different, concepts of the disease particularly in relationship to etiology. The noncommittal eponymic designation has gained general acceptance in the United States at the present time, even though the process is generally regarded as a neoplasm and included with the malignant lymphomas. In the past 4 decades numerous terms have been proposed for the histologie types of Hodgkin's. disease as a result of the attempts to relate the histologie changes to the extremely variable rates of progression of the disease and to provide a prognostic basis for the recognition of potential prolonged survivors. Interest in the importance of the histologie findings in prog nosis was initiated by Rosenthal (31) when he demonstrated the relationship between lymphocytic proliferation and slowly progressive disease and stressed the importance of the frequency of lymphocytes in prognosis. Earlier E wing (7) proposed the term sarcoma for a pleomorphic neoplastic proliferation of ReedSternberg cells. The classical histologie types of Jackson and Parker (11-15), namely paragranuloma, granuloma, and sar coma, are related to many of the findings of Ewing (7) and Rosenthal (31). Subsequently the prognostic importance of the predominant lymphocytic lesions has been supported by the studies of Harrison (9), Lumb (22), Smetana and Cohen (33), Wright (37, 38), and Dawson and Harrison (6), although a variety of terms have been suggested for the association of lymphocytic proliferation with prolonged survival. The dis tinctive character of the predominant lymphocytic proliferation and its contrast to the granuloma type of Jackson and Parker stimulated Smetana and Cohen (33) to question its relationship to Hodgkin's disease. The term reticular lymphoma was proposed by Lumb (22) for this group to emphasize the distinctive histo logie character, and in recognition of its neoplastic potentiality. The nodular character of the lymphocytic proliferation was initially recognized by Rappaport et al. (28), in their classical re-evaluation of follicular lymphoma. They included this nodular proliferation in follicular lymphoma as Type V (follicular lymphoma, Hodgkin's type), although it was acknowledged that this type more appropriately might be included with the para granuloma group rather than with the general group of malignant lymphomas. Neither Croizat et al. (4) nor Winterhalter (36) found definite evidence of a relationship between the course of the disease and the histologie features. The importance of clinical staging in Hodgkin's disease as initially defined by Peters (26) and later refined by Peters and Middlemiss (27) emphasized the prognostic importance of JUNE 1966 1063 Robert J. Lukes and James J. Rutler localized manifestations in Hodgkin's disease and provided the basis for the recent proposal of the possibility of cure in Hodgkin's disease. The significance of the histologie features in untreated Hodgkin's disease in relationship to the clinical stages and survival was re-evaluated in the authors' recent study (R. J. Lukes, J. J. Butler, and E. Hicks, in preparation; Refs. 18, 20), of the World War II cases of Hodgkin's disease in a 15- to 18- year follow-up study. The results of this study reemphasizecl the importance of the lymphocyte in Hodgkin's disease and its inverse relationship to Reed-Sternberg cells, and demonstrated a definite relationship between the histologie features and the clinical stages existing at the time of biopsy. A new histologie type, nodular sclerosis, emerged as an important prognostic group and the regional expression of Hodgkin's disease in the anterior superior mediastinum. These observations on the nodular sclerosing type have been supported by Hanson (8). In the recent historic meeting on Hodgkin's disease in Paris (21), the re-evaluation by Lukes, Nezelof and Gompel (in preparation) of the pretherapy biopsies from the prolonged survival cases from many of the major radiotherapy groups provided evidence that the nodular sclerosing type was of major prognostic significance. The purpose of this presentation will be to consider in detail the numerous histologie expressions of Hodgkin's disease grouped according to the histologie types reported by the authors (18-20) and relate them to the variety of histologie types that appear in the literature. The possible relationship of the histologie findings to the clinical stages, survival, and the recently described immunologie defect in Hodgkin's disease will be presented. Morphology The diversity of the morphologic findings in Hodgkin's disease is well known and the association of abnormal reticulum cell proliferation of the Reed-Sternberg cell type with a variable inflammatory type cellular proliferation represents a unique histologie process. The nature of this process has puzzled pathol ogist* since the initial histologie description of Greenfield. Investigators in the past few decades have been primarily con cerned with the evaluation of the histologie findings in prolonged survival cases for prognostic purposes, and little attention has been given to the study of the significance of the numerous variations in the histologie findings, although the process is generally regarded as neoplastic in the United States. In this consideration of the morphologic findings we will be concerned with the variation in the reticulum cell proliferation, particularly the Reed-Sternberg cell, the numerous histologie types, and the most appropriate terminology proposed for these variants. An attempt will be made to relate the variations in the histologie process to the gross findings, the clinical stages of the disease, the evolution of the histologie process, and the rate of progression of the disease in terms of median survival. Classification of Hodgkin's disease as a neoplasm is based on the generally progressive character of the process, the occasional pleomorphic appearance of the Reed-Sternberg cell, and the tumor-like disseminated masses observed at autopsy that may exhibit infiltrativc features. The indistinguishable appearance at times of the histologie findings of the fulminating terminal phase of Hodgkin's disease with those of histiocytic lymphoma (reticu lum cell sarcoma) has been used as further support for the neoplastic nature of the process. The critical point appears to revolve about the debatable issue whether the Reed-Sternberg cell is a neoplastic cell or simply a modified reticulum cell that at times may become pleomorphic"at which time it is definitely neoplastic. The common occurrence of numerous abnormal reticulum cells, without the distinctive features of classical Reed- Sternberg cells, that appear to represent intermediate or partially developed Reed-Sternberg cells provides support for the latter possibility. It has not been established whether the process, if neoplastic, involves all the cellular components and is a mixed lymphoma as proposed by Lumb (22), Herman (2), and others, or the Reed-Sternberg cell is the only neoplastic component"if indeed it is a neoplastic cell"and the associated histologie com ponents are inflammatory reactions. Definite evidence of neo plasia is observed in a small proportion of cases at biopsy with fulminating disease and a limited number of cases at autopsy where Reed-Sternberg cells predominate and are distinctly pleomorphic. Biopsy specimens in the majority of cases exhibit morphologic expressions of an inflammatory process associated with an increase in the frequency of the Reed-Sternberg cells and a decrease in lymphocytes and other cellular elements with progressive disease. The change in character of the Reed-Stern berg cells with the development of distinctive pleomorphic features provides a basis for suggesting that the evolution of the Hodgkin's disease process may represent the induction of malignant neoplasia. In this situation the cellular and connective tissue components associated with the Reed-Sternberg cells would represent expressions of the host's attempt to counteract the induction of neoplasia. This consideration fits well with the associated variable cellular proliferation and the inverse relation ship between lymphocytes and Reed-Sternberg cells. The possi bility of neoplastic induction in Hodgkin's disease is unanswer able at the present time, but requires thorough consideration and investigation. The reticulum cell proliferation in Hodgkin's disease involves not only the abnormal reticulum cell of the Reed-Sternberg cell type and its variants, but also a reactive histioc3'te that is possibly related to the formation of fibrillar reticulum, the fibroblastic component and eventually fibrous connective tissue. A variety of Reed-Sternberg cells usually can be found in an individual biopsy or autopsy specimen. The frequency and character of Reed-Sternberg cells in our experience appears to be related in some degree to the type of associated cellular pro liferation. Only a few variations of Reed-Sternberg cells, how ever, can be regarded as diagnosticali}' reliable, since benign proliferation of reticulum cells in reactive processes, especially in viral infections, may exhibit large nucleoli and vesicular nuclei, 2 features often associated with Reed-Sternberg cells. Fortu nately multinucleation does not appear to be a feature of the reticulum cell reaction in viral infections, and provides a basis for their differentiation. The 2 most distinctive and reliable features in the identification of Reed-Sternberg cells are the huge inclu sion-like nucleolus and polyploidism, the occurrence of multiple divisions of the nuclei without cytoplasmic division. A few of the more common variations in Reed-Sternberg cells are presented in Fig. 1. Mononuclear forms are usually found in typical lesions of Hodgkin's disease (Fig. la) and also may exhibit the huge inclusion-like nucleolus and a vesicular nucleus. Although the mononuclear type appears to represent a form of the Reed- 1064 CANCER RESEARCH VOL. 26 Pathologyand Nomenclature Stern berg cell, it is not considered to be reliable diagnostic-ally in II istologie Types our experience since it may be confused with the reticulum cells of viral reactions. Lobatecl and binucleated forms (Fig. 1ft) represent manifestations of polyploidism, one of the important distinctive features of Reed-Sternberg cells. A peculiar clear zone about the huge nueleolus is another unusual feature of these cells and presents the nucleus with a vesicular appearance, but it is uncertain whether or not this feature is artifactual. The nuclear chromatin may be delicate and lacy, but it is usualK observed to be compressed at the periphery, at times as a thickened nuclear membrane with a clear halo-like space about the nueleolus. The nueleolus typically is large, almost spherical in appearance, and resembles an inclusion body with a smooth margin. In staining character it varies from eosinophilic to amphophilic, but is of uniform intensity. The cytoplasm is rather inconsistent, both in quantity and staining, although it is most frequently observed to be abundant and lightly eosinophilic to amphophilic. The pleomorphic Reed-Sternberg cell that is Numerous histologie types have been described in the past 3 decades primarily in an attempt to account for the cases with slowly progressive disease or prolonged survival with asympto matic disease. The terms commonly employed for the histologie types resulting from these studies are listed in Table 1 in rela tionship to the predominant histologie findings. In our recent study (18), in which the significance of the histologie features and clinical stages in Hodgkin's disease was evaluated, it was appar ent that there were 6 predominant histologie expressions of untreated Hodgkin's disease for which we proposed the following terms: (a) lymphocytic and/or histiocytic (L & H), diffuse; (6) lymphocytic and/or histiocytic (L & H), nodular; (r) mixed; (d) nodular sclerosis; (e) diffuse fibrosis; (f) reticular. In the following discussion the more commonly employed types de scribed in the literature will be analyzed in comparison with the 6 predominant histologie expressions of Hodgkin's disease. regarded as sarcomatous (Fig. 18) is an unusually large cell with a tendency to extraordinary lobular nuclear variations and Lymphocytic and/or Histiocytic Proliferation multinucleation that appear to represent an extreme degree of polyploidism. There is general agreement on the existence of a histologie Several types of abnormal reticulum cells that are probably lesion composed predominantly of mature lymphocytes. Al related to Reed-Sternberg cells are observed in association with though the term paragranulema is commonly used in the United 2 of the histologie types that will be described in a subsquent section. With lymphocytic proliferation where classical Reed- States, numerous terms have been lymphocytic proliferation in Hodgkin's proposed. In addition, disease occurs usually in Sternberg cells are infrequent and difficult to find, numerous association with varying numbers of reactive histiocytes. These peculiar and abnormal reticulum cells are found with folded cells have abundant, pale, eosinophilic cytoplasm and medium overlapping lobes, with delicate lacy chromatin and small size nuclei with uniformly distributed delicate chromatin (Fig. nucleoli. This type appears to represent a partially modified 7). They are readily differentiated from the variants of the Reed- reticulum cell, and possesses the polyploidism, but not the huge Sternberg cell (Fig. 1). At times a small number of multimicleated nucleoli, of Reed-Sternberg cells. In the nodular sclerosis type, histiocytes are found. The histiocytic component varies widely an unusually large abnormal reticulum cell is found, often in great from scattered individual histiocytes to a predominance of numbers. These cells have abundant pale eosinophilie cytoplasm, histiocytes with only a small component of residual lymphocytes. at times with an area of condensed deeply eosinophilic cytoplasm The lesion composed predominantly of lymphocytes has been adjacent to the nucleus that has a tendency to be excessively the subject of numerous reports, while the lesion where the multilobated with many small individual nuclei. Although these histiocytic component is dominant has been overlooked and distinctive abnormal reticulum cells of nodular sclerosis (Fig. apparently included within the granuloma group. The term 13) are generally numerous and exhibit polyploidism, char lymphocytic and/or histiocytic (L & H) was considered most acteristic diagnostic Reed-Sternberg cells with huge nucleoli, appropriate because of the almost constant occurrence of vesicular nuclei, and amphophilic cytoplasm are often difficult histiocytes in lymphocytic proliferations, the frequency of to find. lesions with a predominance of histiocytes, and the wide spectrum In considering the variations of Reed-Sternberg cells and of lymphocytic or histiocytic proliferation observed in this group. possibly related abnormal reticulum cells it seems that the The term lymphocytic and/or histiocytic (L & H), although number and type of Reed-Sternberg cells appear indirectly somewhat cumbersome, serves to emphasize the frequent, related to the intensity of lymphocytic proliferation. Where prominent histiocytic component and avoids classification of the lymphocytic proliferation is prominent, the number of char predominantly histiocytic lesions as the granuloma type accord acteristic Reed-Sternberg cells is rare, although the peculiar ing to the criteria of Jackson and Parker (11). It is interesting to polyploid reticulum cells with delicate, lacy chromatin may be note that, in a comparison evaluation, over 50% of the L & H numerous. Where lymphocytes appear to be depleted, typical cases of our study (18, 20) fulfilled the criteria for the granuloma Reed-Sternberg cells with characteristic polyploid vescular type on the basis of the frequency of histiocytes when classified nuclei and huge inclusion-like nucleoli are numerous, and at according to the criteria of Jackson and Parker (11). With this times the pleomorphic type may be evident. The distinctive spectrum of lymphocytic and histiocytic proliferation, char abnormal reticulum cells associated with lymphocytic pro acteristic Reed-Stemberg cells are rare, although the peculiar liferation (L & H types) and nodular sclerosis appear to represent abnormal polyploid reticulum cells previously discussed with modified reticulum cells related to Reed-Sternberg cells, but they Reed-Sternberg cells may be relatively numerous. Kosinophils, are not regarded, however, as diagnostically reliable Reed- plasma cells, and mature neutrophils are uncommon or absent. Sternberg cells. There is essentially no fibrosis. JUNE I960 1065 Robert J. Lukes and James J. Butler TABLE 1 RELATIONSHIP OF PREDOMINANTHISTOLOGICFEATURES TO HISTOLOGICTYPES IN THE LITERATURE Histologie types by predominant histologie features (Rets. 18, 20) Histologie types in literature Author and year Lymphocytic and/or histiocytic (L & H) (lymphocytes predominating) u. Diffuse b. Nodular Lymphocytic and/or histiocytic (L & H) (histiocytes predominating) Nodular or diffuse Mixed Nodular sclerosis (collagen formation) Diffuse fihrosis (disorderly reticulum) Reticular a. Reed-Sternberg ing) cells (predominat b. Reed-Sternberg cells (pleomorphic) L &R Early Hodgkin's Paragranuloma Lymphoreticular medul lary reticulosis Benign Hodgkin's Reticular lymphoma Indolent Hodgkin's Follicular lymphoma, Hodgkiu's type Granuloma Granuloma Fibromyeloid reticulosis medullary F &R Granuloma Granuloma with sclerosis R &L Granuloma Reticulo-Hodgkin's Sarcoma Sarcoma 0 As quoted by Offerhaus (25). Rosenthal, 1936 (31) Jackson, 1937 (14) Jackson and Parker, 1944 (11) Robb-Smith, 1947 (30) Harrison, 1952 (9) Lumb, 1954 (22) Symmers, 1958 (34) Rappaport et al., 1956 (28) Jackson and Parker, 1944 (11) Jackson and Parker, 1944 (11) Robb-Smith, 1947 (30) Rosenthal, 193G (31) Jackson and Parker, 1944 (11) Smetana and Cohen, 1956 (33) Rosenthal, 1936 (31) Jackson and Parker, 1947 (11) Lennert, 1957 Ewing, 1928 (7) Jackson, 1937 (14) Lymphocytic and/or Histiocytic (L & H) Type, Diffuse A lymph node exhibiting lymphocytic and histiocytic pro liferation is usuali}' a single, enlarged node that may reach con siderable size and range from 3 to 5 cm in diameter upon biopsy. In the diffuse L & H type the cellular proliferation extends uniformly throughout the lymph node, with compression of the sinusoids and absence of lymphatic follicles (Fig. 2). Occasion ally, a small portion of compressed, distorted, uninvolved lymph node cortex remains in the periphery. The diffuse type frequently exhibits a prominent histiocytic component (Fig. 6), while the nodular type is generally predominantly lymphocytic. When the lymphocytic component predominates in the diffuse type (Fig. 5), the cellular proliferation is composed of mature lymphocytes and closely resembles a well-differentiated lymphocytic lymphoma, the tissue counterpart of chronic lymphocytic leukemia. The 2 processes are differentiated histologically on the basis of an essentially single cell type of proliferation, the small lymphocyte, in lymphocytic lymphoma, with only a rare reticulum cell or other cellular elements. In addition this lymphoma occurs predominantly in patients over 55 years of age and rarely under 45 years. The diffuse L & H type by contrast usually has a histiocytic component and numerous abnormal reticulum cells related to Reed-Sternberg cells and usually occurs in younger patients. The abnormal reticulum cell component that appears to be related to Reed-Sternberg cells is often relatively prominent and may represent as much as 10% of the cell population. It is composed primarily of peculiar large cells with folded, twisted, lobated pale nuclei that have fine, lacy, delicate chromatin and small nucleoli. Characteristic Reed-Sternberg cells with large nucleoli, however, are extremely infrequent, or rare, and it may be necessary to search a number of sections to find typical Reed- Sternberg cells on which to establish a reliable diagnosis. In spection of Table 1 indicates that this group has aroused most of the attention of pathologists as a result of its distinctive histologie character and the association of lymphocyte proliferation with prolonged survival. It should be emphasized that the terms listed refer to a predominant lymphocytic proliferation with a small component of histiocytes. Eosinophils and plasma cells were infrequent or absent. There was little or no fibrosis and necrosis was absent. Almost 30 years ago, Rosenthal recognized the prognostic significance of the predominant lymphocytic pro liferation and the associated relative infrequency of Reed- Sternberg cells, for which the term L & R (lymphocytic and reticulum cell) was proposed. Subsequently, Jackson (14) sug gested that this lesion might represent early Hodgkin's disease, but later Jackson and Parker (11) indicated that this was an unfortunate choice of terms and recommended paragranuloma as a more appropriate designation to indicate a close relationship to Hodgkin's granuloma. The term lymphoreticular medullary reticulosis was proposed several years later by Robb-Smith (30), 10G6 CANCER RESEARCH VOL. 26 Pathology and Nomenclature apparently for the same lesion. The high incidence of survivors at 5 and 10 years and good prognosis of this lesion prompted the proposal of the term benign llodgkin's by Harrison (9) in 1951, in preference to the term paragranuloma. It evolved from a retro spective study of cases with prolonged survival in their group. Histologically the lesion was composed predominantly of small lymphocytes with a prominent component of abnormal reticulum cells. Subdivision of the cellular proliferation by either collagen bands or reticulum fibers into cellular nodules was a common feature. It appears from their photomicrographs and description that the majority of their cases may represent the cellular phase of the nodular sclerosing type with limited collagen formation. This lesion will be considered in a subsequent section. The study was subsequently enlarged, again under the term benign llodgkin's disease by Dawson and Harrison (6). A similar cellular prolifera tion was observed also in nodular distribution in this series, in approximately f of their cases in association with compression of the reticulum fibers about the periphery of the nodules. The resemblance of the nodular proliferation to the type of follicular lymphoma described by Rappaport et al. (28) was noted. The term reticular lymphoma was urged by Lumb (22) for the lesion he regarded as identical to paragranuloma in an attempt to emphasize its distinctive character and definite relationship to Hodgkin's disease. Definite doubt over the relationship of paragranuloma to Hcdgkin's disease was expressed by Smetana and Cohen (33), although the usual predominant lymphocytic lesion with Reed-Sternberg cells was described in their cases of paragranuloma. Evidence that Hodgkin's disease with a pre dominance of lymphocytes has progressed to the disseminated form of Hodgkin's disease recently has been presented by a number of authors, including Wright (37, 38), Lumb (22, 23) and Dawson and Harrison (6). Symmers (34) prefers the term indolent to emphasize the need for caution in prognosis, although he acknowledges its identity with paragranuloma. Lymphocytic and/or Histiocytic (L & H), Nodular In this process the cellular proliferation is aggregated in a vaguely nodular fashion (Fig. 3) and the abnormal polyploid reticulum cells and histiocytes are often concentrated in the central portion of the nodules, though usually not in cohesive clusters. The proliferation is usually overwhelmingly lymphecytic, involving both nodules and internodular tissue. Histiocytes have predominated in the nodular type on only a few occasions in our series. The nodules are generally large, closely situated, and often involve only a portion of the lymph node. The re mainder of the node in these instances is involved diffusely by a cellular proliferation similar to that within the nodules. The nodular character of the lesion is clearly demonstrated in retic ulum stained sections where the reticulum fibers are compressed to the periphery about the nodules (Fig. 4). Typical ReedSternberg cells are rare, although abnormal polyploid reticulum cells with small nucleoli may be numerous. The nodular character of this type of Hodgkin's disease was initially demonstrated by Rappaport et al. (28) under the term follicular lymphoma, Type V (Hodgkin's type), in their classical study on the re-evaluation of follicular lymphoma. It was indicated that the lesion would have been regarded as a paragranuloma if it had lacked nodu- larity. It was suggested furthermore that paragranuloma might TABLE 2 COMPARISONOF HISTOLOOICCLASSIFICATIONS Jackson and Parker (11) Lukes et al. (18, 20) Paragraiiuloma- Lymphocytic and/or histiocytic" a. Diffuse b. Nodular Nodular Granuloma Mixed Diffuse fibrosis Sarcoma- Reticular " L & II types may have predominance of either lymphocytes or histiocytes. be a more ideal designation than to include the lesion with the general group of lymphomas. Dawson and Harrison (6) and Wright (38) have emphasized the resemblance of many of their cases under the term benign Hodgkin's to the group described by Rappaport et al. (28). Mixed Type This histologie type is of heterogeneous composition and occupies a somewhat intermediate position between the pre dominantly lymphocytic proliferation at 1 extreme and lympho cytic depletion with diffuse fibrosis and reticular types at the other. It is composed of histiocytes, mature neutrophils, eosino- phils, plasma cells, histiocytes, and lymphocytes in varying proportions, usually with a slight to moderate degree of dis orderly fibrosis, but without collagen formation (Fig. 8). Reed Sternberg cells and related abnormal reticulum cells are often rather numerous and prominent. Focal necrosis may be present, but is usually not marked. The process generally extends through out the entire lymph node and is associated with obliteration of the lymphatic sinusoids and follicles. Focal involvement by a similar process may extend through portions of a lymph node or be limited to small interfollicular areas, apparently as evidence of early involvement of the node. Delineation of this type from the L & H types at 1 extreme and the lymphocytic depiction types at the other may be somewhat difficult at times. Differ entiation from nodular sclerosis is readily accomplished and appears to depend primarily on the frequency and character of the Reed-Sternberg cells and the degree and character of fibrosis. The mixed type most closely approximates the classical concept of granuloma as presented by Jackson and Parker (11). Granu loma, however, unfortunately incorporates a variety of histologie expressions, including the prominent histiocytic proliferation, the advanced fibrosis types, and the lesions composed predominantly of Reed-Sternberg cells where pleomorphism is absent. The granuloma group includes almost the whole spectrum of cellular proliferations (Table 2) with the exception of the extremes where either lymphocytes predominate or Reed-Sternberg cells are numerous and pleomorphic. Fibromyeloid medullary reticulosis, the term of Robb-Smith (30), apparently represents a group comparable to the granuloma of Jackson and Parker (11). JUNE 1966 1067 Robert J. Lukes and James J. Butler Advanced Fibrosis nodule from the circumscribing collagen bands followed by the Advanced fibrosis in Hodgkin's disease appears to involve 2 formation of cellular connective tissue and finally collagen. distinctive types. The 1st, nodular sclerosis, exhibits orderly bands of dense collagenous connective tissue that has a definite tendency to subdivide lymphoid tissue into isolated cellular nodules. The 2nd, diffuse fibrosis, is characterized by a dis organized type of fibrosis of variable character which may be composed of cellular fibroblastic connective tissue or compact hypocellular fibrillar connective tissue associated with cellular depletion, particularly of lymphocytes. Both types are generally included together in the granuloma group. Smetana and Cohen (33) referred to the lesions that exhibited an advanced degree of fibrosis as granuloma with sclerosis, but did not distinguish between the lesions of nodular sclerosis and diffuse fibrosis. Nodular Sclerosis Diffuse Fibrosis This type appears to represent primarily a histologie mani festation of cellular depletion in Hodgkin's disease involving all cell types with the exception of the Reed-Stemberg cell and specifically involves the lymphocytes. Diffuse fibrosis is the common terminal histologie expression of untreated Hodgkin's disease and is associated with variable numbers of Reed-Stern berg cells and focal necrosis. It constitutes the typical findings noted at autopsy. Although therapy undoubtedly contributes to the cellular depletion and the fibrosis observed at autopsy, a similar lesion frequently is observed in biopsies, particularly from patients in untreated, febrile, toxic Stage III disease. The fibrosis is somewhat variable in appearance, disorderly in retic- This histologie type is characterized by orderly bands of inter ulum fiber distribution, and nonbirefringent in character. It is connecting collagenous connective tissue that subdivides dis generally composed of compact, amorphous, proteinaceoustinctively abnormal lymphoid tissue, partially or entirely, into appearing, hypocellular material that has a fibrillar character at isolated cellular nodules (Fig. 9). The degree of collagen forma times and in general bears a resemblance to precollagen (Fig. tion and the character of the cellular proliferation vary widely, 15). On occasions the fibrosis may be partially or prominently at times even within the same specimen. The entire lymph node fibroblastic (Fig. 16). No bands of collagen appear to be formed. or mass on occasion may undergo spontaneous sclerosis with The process involves lymph nodes irregularly, and small loosely residual evidence of nodularity still apparent. The birfringent cellular portions may remain (Fig. 14) that are usually composed character of the connective tissue readily permits its identifica predominantly of Reed-Sternberg cells. Differentiation from the tion as collagen (Fig. 10). The process at times may be predomi nodular sclerosing type is readily accomplished on the basis of nantly cellular, apparently representing a cellular phase, and the the birfringent,orderly, collagen bands usually surrounding formation of collagen bands and isolation of cellular nodules may cellular nodules and of the distinctive, large, cytoplasmic Reed- be limited to a small portion of the specimen. The cellular pro Sternberg cells in the nodular sclerosing type. Diffuse fibrosis by liferation in nodular sclerosis, although varying widely, is dis contrast has disorderly nonbirefringent connective tissue with tinctive and exhibits similar variations both in the nodules and cellular depletion. the abnormal lymphoid tissue not subdivided by collagen (Fig. 11, 12). The distinctive feature of the cellular proliferation in Reticular nodular sclerosis is the unusually large variant of the Reed-Sternberg cell which has abundant pale eosinophilic cytoplasm with This term is employed to refer to the type of lesion in Hodgkin's well-defined cellular borders that present the appearance of a disease that has a predominant component of Reed-Sternberg Reed-Sternberg cell situated in a lacuna-like space (Fig. 13). cells associated with a mixture of cell types and usualry a small These cells have prominently lobated nuclei, often with numer ous lobes, delicate lacy nuclear chromatin and small to medium size nucleoli. Huge nucleoli, characteristic of diagnostic Reed- Sternberg cells are infrequent and often difficult to find. The distinctive features of the Reed-Sternberg cells of nodular sclero sis are the abundant pale eosinophilic cytoplasm, the well-defined cellular borders that present a lacuna-like appearance, the un usually delicate nuclear chromatin with small nucleoli and the unusual degree of hyperlobation. For a diagnosis of Hodgkin's disease, nodular sclerosing type, binucleated or multinucleated cells with large or huge nucleoli (Fig. 1) are still required. The cellular proliferation accompanying the unusual Reed-Sternberg cells, both within the nodules and in the nonnodular tissue may be predominantly lymphocytic, or of mixed composition with numerous eosinophils or mature granulocytes or both. At times Reed-Sternberg cells dominate the proliferation and often in association with focal necrosis. There is an apparent tendency of the isolated cellular nodules to undergo obliterative fibrosis. The initial phase of this process is the appearance of numerous mature granulocytes associated with the loss of lymphocytes. Next, numerous small vessels extend from the periphery of the amount of disorderly fibrosis. It includes lesions in which the Reed-Sternberg cells may be either pleomoiphic and sarcomatous (Fig. 18) according to the criteria of Jackson and Parker (11), or exhibit a simple numerical predominance of characteristic Reed-Sternberg cells (Fig. 17). The entire lymph node may be loosely cellular and composed predominantly of Reed-Sternberg cells with depletion of other cellular elements. Frequently areas of necrosis are found and at times a portion of the lymph node may exhibit features of diffuse fibrosis. The 2 types, diffuse fibrosis and reticular, appear to be closely related, although at times 1 may predominate to the exclusion of the other. The reticular type is most commonly observed in autopsy material of post-therapy cases or in lymph node biopsies from Stage III disease with systemic symptoms. The pleomorphic ReedSternberg cell proliferation that fulfills the definition of Hodgkin's sarcoma is very uncommon in our experience in untreated cases, and only 1% of the cases of our series exhibited this manifesta tion. Lennert used the term ret-culo-Hodgkin's,according to Offer- house (25), for a somewhat similar lesion which is intermediate between granuloma and sarcoma. The predominance of the 1068 CANCER RESEARCH VOL. 26 Pathology and Nomenclature nonpleomorphic portion of the reticular group in our Feries (18, 19) over the sarcoma type justifies its separation from the granu loma group, but its prognostic similarity to sarcoma provides evidence of their close relationship. TABLE 3 RELATIONSHIPOF HISTOLOGICTYPES TO CLINICALSTAGES GROUHPISSLTOLOGIC CLOINF ICCAASLESSTBAYGE (%)I78053637111938n9*273640273834ill13r8C2823624328 COAFSES2340149974721377DISTRIBUTION Gross Pathology A few brief comments on the gross pathology of lymph nodes and the distribution of lymph node and organ involvement in Hodgkin's disease are believed indicated, particularly where a relationship to the histologie findings appears to exist. In the lymph node exhibiting lymphocytic and histiocytic proliferation (L & H types) evidence of lymph node involvement is generally confined to a single large node or a cluster of enlarged nodes, most commonly in the cervical region. The individual nodes may vary 3-5 cm in diameter, but excision biopsy appears to be the limiting factor for the size of the nodes. The lymph nodes are well defined, nonadherent, soft to moderately firm, and have bulging moist tan to grayish-white cut surfaces. In the nodular sclerosing type, lymph node involvement appears to be limited primarily to an inverted triangular region that includes the anterior superior mediastinum, the scalene, supraclavicular and ower cervical regions. In our series, the nodular sclerosing type at the time of initial involvement was associated with an in cidence of mediastinal involvement 15 times as great in Stage I as in all other types combined and more than twice as frequently when all stages are combined. The nodes may vary extensively, depending upon the degree of collagen formation and, apparently, on the occasional infiltrative character of the cellular prolifera tion. The lesion usually consists of a well-defined firm to hard individual lymph node or densely clustered matted nodes forming a single well-defined large mass. In the mediastinum it may resemble a thymoma radiologically except that it is usually located high in the anterior superior mediastinum. The cut surface typically exhibits a distinctly nodular character, with firm dense retracted grayish-white interconnecting bands, cir cumscribing slightly bulging yellowish-tan areas that may exceed 1.0 cm in diameter (Fig. 19). On a few occasions in our experience the mediastinal masses removed surgically have involved the thymus partially, even though Marshall (24) has shown that thymic involvement in Hodgkin's disease is distinctly unusual in autopsy material. At times in the nodular sclerosing type the lesion may be ill defined, with infiltration of adjacent tissue and organs, and absence of discernible lymph nodal demarcation. The cut surface of these lesions may contain areas of dense, retracted, grayish-white tissue, intermingled with firm grayishwhite, so-called "fish flesh"-appearing, tissue. The classical gross appearance of the lymph nodes in Hodgkin's disease is found in the remaining histologie types, the mixed, diffuse fibrosis, and reticular. When observed at autopsy they may form con tinuous, adherent, irregularly nodular masses that follow the major vessels in the abdomen, encompass the aorta and vena cava and even the adjacent ureters, and extend from the inguinal ligament to the diaphragm (Fig. 20). This involvement provides the morphologic counterpart of the remarkable process recently observed by lymphangiography. Similar massive contiguous involvement may be observed in the thorax extending from the diaphragm to and above the clavicles, about the great vessels, into the hilus of the lungs, over and through the pericardium. IT&NodularDiffuseNodular sclerosisMixedDiffuse fibrosisReticularTotalNO. Lymphocytic and/or histiocytic proliferation. bThis group contains only 2 cases. ' This group consists of 3 cases. Pathologic evidence of the extent of lymph node involvement is available essentially only in autopsy material in which there usually has been extensive modification by a variety of thera peutic agents. The occurrence of continuous masses of lymph nodes at this time does provide support for the belief that Hodgkin's disease may disseminate by direct extension. This evidence, however, is of limited reliability since it is derived from extensively modified advanced disease. The nodular character of the involvement of the spleen (Fig. 21), liver, and bone marrow, represents a type of involvement that is similar to that observed with metastatic tumors or disseminated granulomas. Isolated nodules of varying frequency are irregularly distributed through out these tissues. The predominant histologie character of these disseminated nodules is of the diffuse fibrosis or reticular type with the former usually predominating. Extensive infiltration of organs and extra lymph node tissue, such as the adrenals in retroperitoneal infiltration, may occur, with obliteration of architectural features of the involved organ. Histologically they are usually either the diffuse fibrosis or reticular types, and at times both may be seen in different portions of the process in association with varying degrees of pleomorphic changes in the reticulum cells. This infiltrative aggressive form of Hodgkin's disease has been used as evidence for the neoplastic character of Hodgkin's disease. The Relationship and Survival of Histologie Features to Clinical Stages A brief consideration of the relationship of the morphologic features to clinical stages and survival may shed light on the significance of the morphologic changes. To accomplish this some of the data from our recent report (18, 19) on a 15- to 18-year follow-up study of 377 U. S. Army cases from World War II will be briefly reviewed. The relationship of the histologie types to clinical stages along with the distribution of the cases is recorded in Table 3. In this population of predominantly young adult American males of military age, nodular sclerosis represents the most common histologie type (40%) and the remaining cases are irregularly distributed in the other groups. Consideration of the JUNE 1966 100!) Robert J. Lukes and James J. Butler TABLE 4 prominent lymphocytic depletion and have median survivals of RELATIONSHIP OF HISTOLOGICTYPES AND CLINICAL STAGES TO SURVIVAL 0.4 to 0.6 year, respectively. Nodular sclerosis, which has the largest single group of cases initially observed in Stage I, has a GROHUISPTSOL*L&OGIC median survival of 11 years in Stage I which is similar to the OFCASESO2F3S4U01R4V9I9V74O7R(2yS1r13)A0717ll1Ns2toa3.g1e0s11125.40S7MU.4ER4DV.2II2AV.5NA0L.92.34.0I16.09.511m.0e4d.8i1a.n15.79s.u1rIIv1i2v. al often recorded for the paragranuloma type. Several definite conclusions appear to be indicated from the data that was derived from our re-evaluation study (18, 19) of HNodularDiffuseNodular the significance of the histologie features and clinical stages in Hodgkin's disease. Lymphocytic and histiocytic proliferation is 064.83.22.53.22.73.2III4.3"5.5=1.81.20.40.61.3 associated predominantly with Stage I disease and is associated sclerosisMixedDiffuse fibrosisReticularAll with prolonged median survivals. The lymphocytic depletion types manifested histologically by diffuse fibrosis and the predominant Reed-Sternberg cell proliferation in the reticular type are usually observed in Stage III disease with rapidly casesNo. " Lymphocytic and/or histiocytic proliferation. b Duly 2 cases were in this group; therefore the average was used as more representative. c Only 3 cases were in these groups; therefore an average was used. progressive disease of brief duration. Nodular sclerosis is of major prognostic significance in Stage I since it is the most common histologie type and has a prolonged median survival. Comparison classifications of the same case population using the histologie types of Jackson and Parker (12) indicates that this classification is generally ineffective prognostically in recognizing the majority of prolonged survivals. Since over 90% of the case population were classified as the heterogeneous granuloma type, clinical stages existing at the time of biopsy indicates a definite relationship between the histologie types and clinical stages. The majority of the L & H types were initially observed in Stage I, while diffuse fibrosis and reticular types where lympho cytes are depleted are most commonly in Stage III and in over 80% of the cases in Stages II and III. Nodular sclerosis, which appears to be a regional expression of Hodgkin's disease in the anterior superior mediastinum and adjacent cervical region, apparently may be seen in any clinical stage as the process evolves and yet retains the distinctive histologie features of this type. The mixed type appears to represent a histologie expression of changing disease, with equal distribution clinically in the 3 stages, in an intermediate histologie position between the lymphocytic proliferation of the L & H types and the lympho- cytic depletion of the diffuse fibrosis and reticular types. The relationship of histologie types to clinical stages along with the number of survivals is recorded in Table 4. There is a definite relationship between histologie types and survival. In addition, the majority of survivors at 15 years, 44 cases (79%), were observed in the prognostic/ally favorable groups, the L & H and nodular sclerosing types. The survival period for the L & H types, both nodular and diffuse, is significantly longer than for the remaining types and for the nodular type, is significantly longer than for the diffuse type. The large group of patients composing the nodular scle rosing group also have a significantly longer survival than those with the mixed, diffuse fibrosis and reticular types. Diffuse fibrosis, the type associated with lymphocytic depletion, has a remarkably brief median survival of only 0.9 year. A brief consideration of the median survivals when the histo logie types are combined with the clinical stages in Table 5, keeping in mind the distribution of histologie types and stages, demonstrates several very significant features. The L & H types which occur predominantly in Stage I have prolonged median survivals of 16 and 9.5 years for nodular and diffuse types respectively. This is in marked contrast to the diffuse fibrosis and reticular groups which are usually found in Stage III with correlation of the histologie type and clinical stages was im possible with histologie types of Jackson and Parker. It is believed that results of this study re-emphasize the importance of the lymphocyte in Hodgkin's disease initial!}' demonstrated by Rosenthal (31). Evolution of the Morphologic Process The results of the evaluation of the significance of the histo logie features and clinical stages provide insight into the evolution of the histologie process of Hodgkin's disease. Somewhat similar observations have previously been reported by Custer and Bernhard (5) and others although different terminology was employed. Reconstruction of the histologie evolution of the process from our observations appears possible in all except the nodular sclerosing type, where the spontaneous tendency to undergo sclerosis and the significance of the frequently prom inent Reed-Sternberg cell proliferation has been a difficult problem to unravel. The apparent histologie evolution of the Hodgkin's disease process is summarized in Table 5; the nodular sclerosing type is set aside in a questionable state. It appears that a lymphocytic proliferation, associated with TABLE 5 EVOLUTION OF HISTOLOGICPROCESS IN HODGKIN'S DISEASE L & H - -L& H" (nodular) (diffuse) Diffusefibrosis ?? Nodular sclerosis6 ^ Reticular Lymphocytic"Mixed^Reticular (infiltrative) Total sclerosis " L & H, lymphocytic and/or histiocytic proliferation. 6 Evolution of process with nodular sclerosis is uncertain, although a general parallel appears to exist. 1070 CANCER RESEARCH VOL. 26 Pathology and Nomenclature small numbers of histiocytes and Reed-Sternberg cells, may be the initial manifestation of Hodgkin's disease as Stage I disease. It may persist for a variable period of time, possibly depending upon the effectiveness of the lymphocytic proliferation. When it occurs in nodular fashion it is more likely to present clinically as localized Stage I disease, persist for considerable periods, and possibly remain unchanged. When the proliferation is dif fuse, histiocytes are often more numerous and extension may occur with the appearance of Stage II disease. The appearance of eosinophils, noncollagenous connective tissue, and increased numbers of Reed-Sternberg cells presents the features of the lesion designated the mixed type, which appeal's to herald the onset of a changing host response and the beginning of dissemi nated disease. The mixed type is regarded as a histologie expres sion of changing disease since it is encountered with equal fre quency in each stage. The next phase in the evolution of the histologie process appears to be the depletion of lymphocytes, which may occur at varying rates and is associated with either the appearance of diffuse fibrosis or a marked increase in the number of Reed-Sternberg cells. Although this change occurs without therapy, cellular depletion and diffuse fibrosis also result from local and systemic therapeutic measures. Reed- Sternberg cells, when predominant, may be pleomorphic and may participate in an infiltrative process and fulfill the criteria for the sarcoma type. The evolution of the process in the nodular sclerosing type is uncertain at the present time, although the natural tendency of the nodules to undergo sclerosis is readily apparent. It appears, however, that there is an association of predominantly lympho cytic lesions with a well-defined nodular sclerosing process. The appearance of fibrosis within the nodules, with loss of lympho cytes, however, does not seem to have the same significance as diffuse fibrosis elsewhere, but represents part of the sclerosing process. An aggressive infiltrative form of nodular sclerosis has been observed on occasions in which the process is ill defined, locally infiltrative, and composed predominantly of abnormal reticulum cells of the Reed-Sternberg type, with residual colla gen bands or isolated nodules still in evidence in part of the specimen. Further study of this lesion is necessary to clarify the variations of this process and the phases in the evolution of the process. The individual nodules appear to evolve from a pre dominantly lymphocytic proliferation with distinctive abnormal reticulum cells scattered through the central portion of the nodules to total sclerosis that is almost completely devoid of cellularity. The initial modification of the cellular nodule begins with the occurrence of proliferating vessels from the periphery of the nodules, associated with gradual loss of lymphocytes, often in association with infiltration of numerous mature granulocytes and marked increase in abnormal reticulum cells. At this point it seems that the nodule may either progress to total sclerosis or undergo central necrosis. The disseminated foci of Hodgkin's disease, particularly in reticuloendothelial organs, have a fairly consistent histologie ap pearance and distribution. They are characterized by diffuse fibrosis, associated with a variable number of abnormal reticulum cells of the Reed-Sternberg type. Other cell types are uncommon. At times either Reed-Sternberg cells or diffuse fibrosis may pre dominate. The lesions in the spleen, bone marrow, and liver are distributed in a fashion similar to disseminated granulomas and are found primarily in the Malpighian corpuscles in the spleen, as isolated nodules in the hematopoietic marrow, and usually in portal areas in the liver. In other organs disseminated foci also appear to occur initially in preexisting lymphoid tissue sites, such as the peribronchial rymphoid tissue in the lungs, and the lamina propria of the gastrointestinal tract. These observations on the generalized sites of Hodgkin's disease suggest that it disseminates in a fashion similar to granulomas of infectious disease as lympho cytic depletion develops. Comparison of Histologie Classifications The classifications of Jackson and Parker (11) and the authors are related schematically in Table 2 and were analyzed in a comparative study (18-20) of our cases. It is apparent that the granuloma type of Jackson and Parker incorporates most of the histologie expressions of Hodgkin's disease and includes nodular sclerosis, mixed, and diffuse fibrosis types, part of the L & H types, and almost all of the reticular type. Classification of the 377 cases in our recent study according to the criteria of Jackson and Parker (11) resulted in 30 cases (8%) being classified as paragranuloma, 344 cases (91 %) as granuloma, and 3 cases (1%) as sarcoma. This represents a distribution similar to that re ported in the majority of studies (1). It is apparent that the granulomatous type is a heterogeneous group that encom passes a variety of histologie expressions and includes the over whelming majority of the cases of all reported series. The dis tribution of the same group of cases into the 6 histologie types of the authors is listed in Table 4 with the median survival and number of survivors at 15 years. The prognostic value of the classification of Jackson and Parker (11) is limited to the para granuloma group, which included only 12 (21%) of the 56 sur vivors in our study, while the remaining 44 survivors (79%) at 15 years exhibited features of granuloma. This finding repre sents dramatic evidence of the limitations of the classification of Jackson and Parker in prognosis. The prolonged median sur vivals of 11.2 years with paragranuloma and O.G year with sarcoma are significant, but the groups are small. Discussion The numerous histologie expressions found in Hodgkin's dis ease appear to represent manifestations of differences in the host's response rather than a mixed lymphoma as suggested by Lumb (22) and Berman (2). Evidence of the importance of the lymphocyte in the response of the host is provided by the asso ciation of lymphocytic proliferation of the L & H types with clinical Stage I and prolonged median survival, and of the lymphocytic depletion types, diffuse fibrosis and reticular, with Stage III and rapidly progressive disease. The role of the lym phocyte in Hodgkin's disease appears to be related to the re cently observed immunologie defect that is manifested by an inability to develop delayed hypersensitivity (17, 32), delay in homograft rejection (16), and the depletion in lymphocytes in the inflammatory reactions in the skin window of Rebuck (29). Support for a lymphocyte defect is becoming apparent also in the form of defective lymphocyte transformation with phytohemagglutinin in the studies of Hirschhorn et al. (10), Aisenberg (1), and R. J. Lukes, J. W. Parker, and H. Wakasa (in prepara- .IUNE 19GC 1071 Robert J. Lukes and James J. Butter tion). The inverse relationship of lymphocytes and Reed- Sternberg cells observed by Rosenthal (31) and the authors (18-20) is a dramatic demonstration of the interplay of the host factors and the basic alteration of the disease as manifested by the Reed-Sternberg cell. From the authors' experience with histo logie material from over 3000 cases, the basic process seems to involve the Reed-Sternberg cell, while the associated cellular and connective tissue features represent expressions of the attempted response of the host. The association of a variety of inflammatory type cellular pro liferations with Reed-Sternberg cells raises a serious question about the neoplastic nature of the process. The variation in the character and frequency of Reed-Sternberg cells in the various histologie types provides the basis for the proposal that the Hodgkin's disease process may represent the gradual induction and development of malignant neoplasia and that the numerous histologie types reflect differences in the effectiveness of the host's ability to prevent the neoplastic induction. If this proposal is correct, fully developed neoplasia may be limited to the small proportion of cases in the reticular group with definite pleo- morphism. The majority of the terms in the literature for the histologie manifestations of Hodgkin's disease have been proposed pri marily for a predominant lymphocyte proliferation that may be either nodular or diffuse. This group includes the L & R type of Rosenthal (31), paragranuloma of Jackson and Parker (11), lymphoreticular medullary reticulosis of Robb-Smith (30), indo lent Hodgkin's disease of Symmers (34), and follicular lymphoma, Hodgkin's type, of Rappaport et al. (28). These terms with the exception of that of Rosenthal (31), of Robb-Smith (30), and Rappaport et al. (28), have resulted from retrospective studies that attempted to evaluate the significance of this distinctive histologie lesion and relate it to the prolonged survivals for prog nostic purposes. The opportunity for systematic evaluation of the significance of the histologie features in a large group of cases of Hodgkin's disease with long term follow-up has been limited, particularly in relationship to the clinical stages and in light of the recent immunologie developments. In our recent study (18-20) in which this systematic approach was used, the histo logie findings appeared to fall into 6 histologie groups based on the predominant histologie feature. Undoubtedly greater separa tion could have been accomplished, but it is questionable whether it would have served a useful purpose. The groupings selected were the result of several basic considerations: (a) the importance of the lymphocyte and the inverse relationship of the frequency of lymphocytes to Reed-Sternberg cells; (6) the occurrence of 2 distinctive types of fibrosis in Hodgkin's disease"the formation of collagen in nodular sclerosis, and a disorderly fibrosis asso ciated with lymphocytic depletion in diffuse fibrosis; (c) the reali zation that a number of types of reticulum cells are found in Hodgkin's disease, including a variety of abnormal reticulum cells apparently related to the Reed-Stemberg cell, that appear to be distinctive for several of the histologie types; and (d) the consistent occurrence of reactive histiocytes with lymphocytic proliferations and often as a major component. Establishment of the L & H types permitted the recognition of the prognostic importance of the histiocytic component, which more than doubled the size of this favorable prognostic group with lymphocytic proliferation in our series of cases. The signifi cance of the relationship of lymphocytes and histiocytes is un clear, although the presence of a prominent number of histiocytes seems to indicate a less effective host response. The proposal that lymphoeytic and histiocytic proliferations should be considered jointly appears justified to the authors. This belief is based on the following observations: (a) lymphocytes and histiocytes occur consistently together in varying degrees and are difficult to sepa rate; (6) the proliferation of lymphocytes or histiocytes when either predominates may be nodular or diffuse; and (c) the L & H lesion is associated with Stage I disease. Recognition of the diffuse and nodular types of L & H seems clearly indicated from the striking difference in the median survival recorded in Table 4, with 7.4 years for diffuse and 12.4 years for nodular. The nodular character of the predominantly lymphocytic pro liferation was demonstrated originally by Rappaport, Winter, and Hicks (28) as a Hodgkin's type of follicular lymphoma. These authors, however, acknowledged that the process might be more appropriately incorporated with the predominantly lymphocytic proliferations of Hodgkin's disease, a view with which we definitely agree. The nodular character of the proliferation is vague and not striking, and may be easily overlooked. It is readily recognizable, however, on reticulum stains as demonstrated by Wright (38) and Dawson and Harrison (6). The descriptive term, "lymphocytic and/or histiocytic (L & H) with nodular and dif fuse types," is believed to be more appropriate than those previ ously reported since it characterizes the histologie appearance, emphasizes the important histiocytic component, and permits the identification of twice the number of prolonged survivors in our study (18, 20). The desirability of a histologie descriptive term has been stressed previously by Eonefant (3) and others, to avoid the various prognostic and conceptual terms prevalent in the literature. The term "paragranuloma" is therefore un desirable since it is not a histologie term and does not recognize the nodular or diffuse variations or the histiocytic component found in the L & H types. Advanced degrees of fibrosis in Hodgkin's disease have been included in the past under the old term, "classical Hodgkin's disease" or in the "granuloma type" of Jackson and Parker (11, 12). It was emphasized as somewhat distinctive by Smetana and Cohen (33) by the term "granuloma with sclerosis," but this term included the 2 distinctive types of advanced fibrosis identi fied by the authors (18-20), nodular sclerosis and diffuse fibrosis. Through the years the prognostically favorable nodular sclerosis has been combined with the rapidly progressive diffuse fibrosis as a single group of advanced fibrosis and more recently have been included within the granuloma type. The failure to separate these lesions undoubtedly accounts for the debated significance in the past of advanced fibrosis in Hodgkin's disease. Rosenthal (31) many years ago, however, emphasized the unfavorable nature of fibrosis in his F & R type, which was never accepted but now appears to be related to diffuse fibrosis. Nodular sclerosis and diffuse fibrosis are readily separable histologically. Nodular sclerosis is identified by the occurrence of birfringentcollagen band formation with a tendency to nodule formation and the presence of distinctive large cytoplasmic Reed-Sternberg cells. Diffuse fibrosis exhibits cellular depletion and disorderly non- birefringent loose hypocellular connective tissue. The distinctive histologie character and prognostic significance of nodular sclerosis has been supported by Hanson (8). At the recent Paris 1072 CANCER RESEARCH VOL. 26 Pathology and Nomenclature meeting on Hodgkin's disease, nodular sclerosis emerged as the most significant prognostic-ally of the histologie types in the re view (R. J. Lukes, C. Xezelof, and C. Compel, in preparation) of the pretherapy lymph node biopsy material from the prolonged survival cases collected from many of the major radiotherapy series of cases of Hodgkin's disease. The mixed type appears to be useful to identify the histologie type intermediate between the lymphocytic and histiocytic pro liferations at 1 extreme and the lymphocytic depletion types, diffuse fibrosis and reticular types, at the other extreme. The sarcoma type of Jackson and Parker (11) is histologically dis tinctive, and a separate designation may be justified on this basis. However, the infrequency of this type in biopsy specimens "1% in our series"and in autopsy material where there is ex tensive therapeutic modification, provided sufficient evidence for the authors to include the lesion in the reticular group. Further more, the remaining cases of the reticular group appear in general to present a relatively similar rate of progression, par ticularly in Stage III disease. The effectiveness of the histologie classification proposed by the authors will ultimately be determined by the ea.se of applica tion and the prognostic usefulness for other workers. These his tologie classification have proven even more effective as a basis for evaluating the state of the disease and in estimating prognosis during the past few years in the authors' experience than in our reported study because of more ideal control over the quality and selection of biopsies. The commonly emphasized variability of the histologie findings in different sites in Hodgkin's disease that has caused considerable debate now can be answered on the basis of the histologie observations of the authors when consid ered in relationship to the clinical states. Differences in the histo logie findings in 2 sites are believed to reflect changing disease which is related to the existence of lyinphadenopathy in more than 1 area, e.g., Stage II or III disease. Differences in the find ings in a single lymph node in Stage I also may indicate that the rate of progression and the state of the host are changing. Our experience with biopsies of recurrent lyinphadenopathy in a single region in patients with prolonged survival, however, demonstrates a maintenance of histologie type, 1 case exhibiting the same L & H nodular process in 5 biopsies over a period of 10 years. The relationship of the histologie findings to the clinical stages reemphasizes the importance of staging and provides evidence that the clinical stages are dependent on the state of the host, which is reflected \>y the histologie findings. A question has been raised whether the correlation in our case material between the histologie type and prognosis is not attributable to the correla tion of the histologie type and anatomic extent and that there fore, the prognosis is related to the anatomic extent. This con sideration, in fact, is the crux of our proposal, but with an im portant basic difference in the interpretation. The histologie changes do appear to be related to the anatomic extent of the disease. It seems to the authors, however, that the anatomic TABLE (> RELATIONSHIPOF RATE OF PUOGKESSIOTNO THE CLINICALAND HISTIOLOGICFACTORSIN HODGKIN'SDISEASE TypeQuiescentChanginv(gyivPr)ar9ol-g1r5es3su-sr6iv0e.5M-(1ed.di5siCatrnliibnuictiasoltna)gieII symptoms00+HmiastnoilfoegstiaetionsL IIIIIand nod&ulHarL dif&fusHeNodular sclerosisNodular sclerosisMixedNodular and IIISystemic sclerosisMixed1 fi)bifrusiusnReeticular extent and the rate of progression are related to the state of the host, which is reflected by the histologie type. It therefore ap pears that the anatomic extent or clinical stage is the result of the state of the host and the histologie type rather than the reverse. Together the histologie types and the clinical stages provide an effective basis for prognosis as demonstrated in the prog nostic schema, Table 6, from the authors' study, particularly when systemic symptoms are used as criteria to modify staging. From this summaiy in Table 6 it appears that Hodgkin's disease occurs essentially in 2 forms, quiescent and progressive, with intermediate changing disease. Quiescent disease is associated with the histologie expressions of the L & H and nodular sclerosis types and with clinical Stage I. Progressive disease is asso ciated with the lymphocytic depletion types, diffuse h'brosis and reticular, and with Stages II and III and systemic symptoms. Nodular sclerosis may be found in any form as a regional ex pression of Hodgkin's disease, but it has emerged as a lesion of major prognostic importance in Stage I, where it is the most frequent histologie type and has a median survival similar to the L & H types. Consideration of the histologie types as expression of the state of the host and their relationship to the clinical stages provides a basis for suggesting that the effectiveness of therapy and the possibility of cure, therapeutic or spontaneous, may be largely dependent on the state of the host. Undoubtedly the accuracy of prognosis and the evaluation of the status of indi vidual patients will be greatly enhanced by the addition of immunologie studies as another parameter of the prognostic schema in Table 6. The importance of the lymphocyte in the histologie process of Hodgkin's disease, the recently demon strated immunologie defect involving the lymphocyte, and the initial observations of defective lymphocyte transformation with phytohemagglutinin emphasize the key role of the lymphocyte in the Hodgkin's disease process and the need for intensive in vestigation to elucidate the precise nature of the lymphocyte abnormality. References 1. Aisenberg, A. C. Quantitative Estimation of the Reactivity of Normal and Hodgkin's Disease Lymphocytes with Thymidine-2-14C. Nature, 206: 1233-35, 1965. JUNE 1900 2. Herman, L. Malignant Lymphomas"Their Classification and Relation to Leukemia. Blood, 8: 195-210, 1953. 3. Bonefant, J. L. La lympho-reticulose medulliar chronique 1078 Robert J. Lukes and James J. Butler inaligne avec syndrome Hodgkinien (paragranulome). Bull. Assoc. Franc. Etude Cancer, 296-315, 1954. 4. Croizat, P., Ponthus, P., Papillon, J., Revol, L., Dargent, M., Pinet, F., Kuentz, M., and Lenobile, E. Le prognostique de la maladie de Hodgkin. Presse Med., 66: 1135-38, 1958. 5. Gster,R. P., and Bernhard, W. G. The Interrelationship of Hodgkin's Disease and other Lymphatic Tumors. Am. J. Med. Sci., oe662:5-42, 1948. 6. Dawson, P. J., and Harrison, C. V. A Clinicopathological Study of Benign Hodgkin's Disease. J. Clin. Pathol., H: 219-31, 1961. 7. Ewing, J. Neoplastic Disease"A Treatise on Tumors, Ed. 3, p. 405. Philadelphia: W. B. Saunders Co., 1928. 8. Hanson, T. A. S. Histologien! Classifications and Survival in Hodgkin's Disease. A Study of 251 Cases with Special Refer ence to Nodular Sclerosing Hodgkin's Disease. Cancer, 17: 1595-1603, 1965. 9. Harrison, C. V. Benign Hodgkin's Disease. J. Pathol. Bac- teriol. 64: 513-18, 1952. 10. Hirschhorn, K., Schreibman, R. R., and Silzach, L. E. In- Vitro Studies of Lymphocytes from Patients with Sarcoidosis and Lymphoproliferative Disease. Lancet, 2: 842-43, 19f>4. 11. Jackson, H., and Parker, F. Hodgkin's Disease. I. General Considerations. New Engl. J. Med., 230: 1-8, 1944. 12. - ". Hodgkin's Disease. II. Pathology. Ibid., 2S1: 35-44, 1944. 13. . Hodgkin's Disease and Allied Disorders. New York: Oxford University Press, 1947. 14. Jackson, H., Jr. The Classification and Prognosis of Hodgkin's Disease and Allied Disorders. Surg. Gynecol. Obstet., 64: 465-67, 1937. 15. Jackson, J. Hodgkin's Disease and Allied Disorders. New Engl. J. Med., 220: 26-30, 1939. 16. Kelly, W. D., Lamb, D. L., Varco, R. L., and Good, R. A. An Investigation of Hodgkin's Disease with Respect to the Problem of Homotransplantation. 187-202, 1960. N. Y. Acad. Sci., 87: 17. Lamb, D., Pilney, F., Kelly, W. D., and Good, R. A. Com parative Study of Incidence of Anergy in Patients with Carcinoma, Leukemia, Hodgkin's Disease and Other Lymphomas. J. Immunol., 89: 555-58, 1962. 18. Lukes, R. J. Relationship of Histologie Features to Clinical Stages in Hodgkin's Disease. Am. J. Roentgenol., 90: 944-55, 1963. 19. . Histologie Features and Clinical Stages. J. Am. Med. Assoc. (Current Concepts in Cancer No. 1), 190: 914-15, 1964. 20. Lukes, R. J., Butler, J. J., and Hicks, E. B. Le pronostic de la Hodgkin d'aprs la varithistologique et le stade clinique. Rledes ractionsde l'hte. Nouvelle Rev. Franc. Hematol., 6: 15-22, 1966. 21. Lukes, R. J., Compel, C., and Nezelof, C. Le diagnostique histopathologique de la maladie de Hodgkin. Analyse pr liminaire d'une tudeconduite l'aveugle sur 395 observations par trois pathologistes de nationalit diffrente.Ibid., 6: 11-14, 1966. 22. Lumb, Ci. D. Tumours of Lymphoid Tissue. Edinburgh and London: E. & S. Livingston, Ltd., 1954. 23. Lumb, G. D., and Newton, K. A. Prognosis in Tumors of Lymphoid Tissue, an Analysis of 602 Cases. Cancer, 10: 976- 993, 1957. 24. Marshall, A. E., and Wood, C. Hodgkin's Disease"Involve ment of Thymus. J. Pathol. Bacterio!., 73: 163-66, 1957. 25. Offerhouse, L. Borderline Cases of Hodgkin's Disease. Proef- st'hrift, University of Amsterdam, 1957. Van Gorcum & Co., N. V. 26. Peters, M. V. A Study of Survivals in Hodgkin's Disease Treated Radiologically. Am. J. Roentgenol. Radium Therapy & Nuclear Med., 63: 299-311, 1950. 27. Peters, M. V., and Middlemiss, K. C. H. Study of Hodgkin's Disease Treated by Irradiation. Ibid., 79: 114-21, 1958. 28. Rappaport, H., Winter, W. J., and Hicks, E. B. Follicular Lymphoma. A Re-evaluation of its Position in the Scheme of Malignant Lymphoma, Based on a Survey of 253 Cases. Cancer, 9: 792-921, 1956. 29. Rebuck, J. W., Monto, R. W., Monaghan, E. A., and Riddle J. M. Potentialities of the Lymphocyte, with an Additional Reference to its Dysfunction in Hodgkin's Disease. Ann. N. Y. Acad. Sci., 73: 8-38, 1958. 30. Robb-Smith, A. H. T. In: S. C. Dyke (ed.), Recent Advances in Clinical Pathology, Chap. 34, p. 360. London: J. & A. Churchill, Ltd., 1947. 31. Rosenthal, S. R. Significance of Tissue Lymphocytes in Prognosis of Lymphogranulomatosis. 628-46, 1936. Arch. Pathol., el: 32. Schier, W. W., Rother, A., Ostroff, G., and Schrift, M. H. Hodgkin's Disease and Immunity. Am. J. Med., 20: 94-99, 1956. 33. Smetana, H. F., and Cohen, B. M. Mortality in Relation to Histologie Type in Hodgkin's Disease. Blood, //: 211-24, 1956. 34. Symmers, W. St. C., In: R. W. Raven (ed.), Cancer, Vol. 2, Chap. 24, p. 478. London: Butterworth & Co., Ltd., 1958. 35. Wallhauser, A. Hodgkin's Disease. Arch. Pathol., 16: 522-62; 672-712, 1933. 36. Winterhalter, K. H. Verlauf und Prognose der Lympho- granulomatose anhand von 140 Fallen. Doctoral dissertation University of Zurich, 1961. 37. Wright, C. J. E. Hodgkin's Paragranuloma. Cancer, 9: 773-77, 1950. 38. " ". The Benign Form of Hodgkin's Disease (Hodgkin's Paragranuloma). J. Pathol. Bacteriol., 80: 157-71, 1960. FIG. 1. Variants of Reed-Sternberg cells with large inclusion-like nucleoli, vesicular nuclei, thick nuclear membranes, a, Mononuclear; 6, bilobed and lobating; r, so-called "mirror image" bilobed type; and d, multinucleated type. The mononuclear type is not regarded as diagnostically reliable. LACH S-65-13924. H & E, X 850. FIG. 2. L & H diffuse: numerous histiocytes are scattered individually and in small clusters throughout a predominantly lymphocytic proliferation. AFIP Neg. 57-4423. H & E, X 40. FIG. 3. L & H nodular: the predominantly lymphocytic proliferation is aggregated in a vaguely nodular pattern. AFIP access. 1024731. H & E, X 20. FIG. 4. L & H nodular: the nodular character of the cellular proliferation is clearly evident in reticulum-stained sections, with com pressed reticulum fibers in the periphery of the nodules. Gomori reticulum stain. AFIP Access. No. 1024731. X 55. 1074 CANCER RESEARCH VOL. 26 Pathology and Nomenclature JUNE 196(> . , .-/.,':,t -''?s'""- , f s. Sj '. \ . .' - IO?.1) Robert J. Lukes and James J. Butler FIG. 5. L & H diffuse: large histiocytes are scattered throughout this predominantly well-differentiated lymphocytic proliferation. AFIP Neg. 57-16885.H & E, X 150. Fio. 0. L & H diffuse: histiocytes are present in almost equal proportions with lymphocytes. AFIP neg. 57-10780.II & E, X 150. FIG. 7. Reactive histiocytes of the L & II types with a variable amount of cytoplasm, medium sine nuclei with delicate chromatin and small nucleoli. AFIP Neg. 03-5613.H & E, X 400. FIG. 8. Mixed type: a variety of cellular components and disorderly distributed fine fibrillar connective tissue is found in the mixed type. AFIP Neg. 57-16819.II & E, X 150. CANCEH RESEARCH VOL. 26 Pathology and Nomenclature FIG. 9. Nodular sclerosis: the sclerosing and nodular character of the process is evident. AFIP Neg. (il-1658. H & E, X 8. FIG. 10. Typical nodule of nodular sclerosing type: a, Collagen bands partially circumscribe the typical cellular nodule in which large pale reticuhim cells are situated in lacuna-like spaces. LACH S65-4895. H & E, X 35. b, The birfringent character of the collagen s'demonstrated by polarized light. LACH SG5-4895. X 35. JUNE I960 1077 Robert J. Lukes and James J. Butler V -iiTcJ. ."- ' '^r7 v- *,."~**". \ g'C^*;.},,a-J.-"r >: . ...:.;a - ^MT_flrflb ^NTfij..*- FIG. 11. Nodular sclerosis: the large Reed-Sternberg cells are situated in lacuna-like spaces in a typical partially circumscribed cellular nodule. LACH S 05-4895. H & E, X 55. FIG. 12. Nodular sclerosis: a typical nodule formation without circumscription by collagen bands. AFIP access. 940771. H & E, X 100. FIG. 13. Nodular sclerosis: the distinctive large variant of Reed-Steruberg cells with abundant pale cytoplasm, prominent lobation, and sharp cellular borders characteristically found in this type. AFIP access. 940771. II & K, X 350. 1078 CANCER RESEARCH VOL. 26 Pathology and Nomenclature "'i*^ , - -, - , , :*Rg 1- 15 FIG. 14. Diffuse fibrosit:he typical hypocellular connective tissue with residual sinusoids is associated with a residual small, mod erately cellular, partially fihrotic area. AFIP Neg. 57-10817.H & E, X 40. FIG. 15. Diffuse fibrosis: compact hypocellular, partially hyalinized, connective tissue has a precollagen-like appearance. AFIP Neg. 57-10817.II & E, X 150. FIG. 10. Diffuse fibrosis: cellular fibroblastic connective tissue occurs at times in this type. LACH 70601.H & E, X 150. JUNE 1906 1079 If oberi J. Lukes and James J. Butler FIG. 17. Reticular: X 150. FIG. 18. Reticular, 90100. X 150. a variety of Keed-Sternberg cells represent the prominent component of this lesion. AFIP access. 854521. II & E, pleomorphic: numerous pleomorphic Reed-Sternberg cells represent the predominant component. AFIP access. FIG. 19. Nodular sclerosis: the bulging nodular character with retracted bands is evident in the cut surface of this mediastinal mass. AFIP Neg. 50-1652. 1080 CANCER RESEARCH VOL. 26 Pathology and Nomenclature FIG. 20. Massive retroperitoneal nodes represent the gross pathologic counterpart to positive lymphiingioKi'iiphiu studies in this partially eviscerated abdomen. The costal margin is visible at the upper efatnd the pleural space iutpper right. AFIP Access. 165C1G. 21 FIG. 21. Multiple irregularly distributed nodules in the spleen characterize organ involvement. AFIP Neg. 61-1504. JUNE I960 1081