- Email: [email protected]
Histopathological classification of Hodgkin's lymphomas
Annals of Oncology 3 (Suppl. 4): S31-S33, 1992. O 1992 Kluwer Academic Publishers. Primed in the Netherlands.
Original article Histopathological classification of Hodgkin's lymphomas Results from the reference pathology of the German Hodgkin Trial J. Bernhards,1 R. Fischer,2 K. Hiibner,3 E.-W. Schwarze4 & A. Georgii' 1
Patholog. Inst., Med. Hochschule Hannover, Kliniken Dortmund, Germany
2
Patholog. Inst., Universitdt Koln, -1 Patholog. Inst., Universitdt Frankfurt, * Patholog. Inst.,
Introduction The German Hodgkin Therapy Trial is a multicenter clinical trial evaluating the therapeutic effects of different radio- and chemotherapy in 3 separate stageoriented studies [1, 2]. Revisitation of diagnostic biopsies was considered to be an obligate part of trial design according to experiences described in the literature [3]. As interobserver disagreement is a well-known phenomenon in the diagnosis and classification of lymphomas [3], it was decided to establish a pathology panel instead of a single reference pathologist. Materials and methods Diagnostic biopsies of up to now 1,140 patients were obtained from the primary pathologists as paraffin blocks. Sections were performed and 4 were distributed to each pathologist. The 4 histopathologists of the panel have reviewed individual stainings from these sections and classified them individually according to the classification system and registered them by codes (Table 1). Dissent cases were revisited by workshop discussions on the microscope achieving a consensus diagnosis. Subtyping of nodular sclerosing (NS) Hodgkin's disease (HD) was achieved according to the criteria of Bennett and MacLennan |4-6).
Table I. System of final classification by a panel of 4 histopathologists from 1,140 cases primarily diagnosed as Hodgkin's disease by individuals from diagnostic biopsies. Code
System of classification
n
%
A. Hodgkin's Disease Clear subtypes 1 Lymphocytic Predominance LP.HD NS l.HD 2.1 Nodular Sclerosis Grade I NS 2.HD 2.2 Nodular Sclerosis Grade II MC.HD Mixed cellulanty 3 Lymphocytic depletion LD.HD 4 Epitheloid cell predominance ECP.HD Unclassifiable Hodgkin 6 Due to insufficient technique 7 Due to unusual features 10.1
Observer's dissent in subtyping
Total of A B. Unclassifiable Lymphomas 8.1 Due to insufficient technique 8.2 Due to unusual features 10.2 Dissent whether HD or NHL
31 588 72 159 8 39
2.7
51.6 6.3
13.9 0.7 3.4
51 24 73
4.5 2.1 6.4
1045
91.7
32 23 17
2.8 2.0 1.5
32 1
1.9 0.1
95
8.3
1140
100.0
C. No Hodgkin's Disease
Results Hodgkin's lymphoma (HD) could be confirmed in 1,045/1,140 cases (91.7%). Non-Hodgkin lymphomas (NHL) were revealed in 22 cases (1.9%), reconfirmed
9 11
Non-Hodgkin's Lymphoma (NHL) No malignancy
Total of B and C Total of all
Downloaded from http://annonc.oxfordjournals.org/ at Florida Atlantic University on February 3, 2015
Summary. Diagnostic biopsies of 1,140 previously untreated 13 HD of unclassifiable subtypes, 6.3 of not certain HD, 1.9 patients with Hodgkin's lymphoma from the German Non-Hodgkin Lymphoma, 1 case of non malignancy. GradHodgkin Therapy Trial were evaluated by a panel of 4 histo- ing of NS.HD into 2 subgroups according to the British claspathologists. Each case was classified by consensus of the sification differed conspicuously by 84.5% versus 15.5% and four according to an extended Rye-System including the 71.6% versus 28.4% in British results. This divergency is diversifying of NS.HD and the unclassifiable cases. The inter- explained by interobserver disagreement ranking from 43% observer agreement rate was 92.1% among the panel mem- to 85%. bers regarding the final classification. Primary Hodgkin diagnosis was approved in 91.7% (1045/1140 cases). The distribution of the 1,140 cases within this system was (in %) as Key words: Hodgkin's disease, histopathology, interobserver follows: 2.7 LP.HD, 57.9 NS.HD, 17.3 MC.HD, 0.7 LD.HD, disagreement
32
by markers. One single case (0.1%) provided no evidence of malignancy. In 73 cases (6.4%) the panel was unable to classify reliably or the panel members disagreed on individual classification after discussion, including phenotyping as well as clinical data (Table 1). Almost all cases of NHL were considered as peripheral T-cell lymphomas or large cell anaplastic lymphomas. Most of these had been diagnosed as MC.HD or LD.HD initially (Table 2).
sified by the individual panelist ranged from 95.4% (panelist 1) to 89.5% (panelist 2) whereas in NS II the range was from 84.8% (panelist 2) to 43.5% (panelist 1) (Table 3). Table 3. Interobserver agreement comparing the individual versus the final classification typing 504 NS.HD cases. Panelist
Table 2. Comparison of final panel classification to primary individual diagnosis. Panel classification
31 660 198 8 148
LP
NS
MC"
25 9
2 525 23 3 58
4 111 158
20
12
15
95
II Confirmed to primary subtype ratio 716/1140 25/72 % 62.8 34.7
525/631 83.2
LD
UCh
3 61
8 5 2 9
6
37
18
7
158/374 42 2
2/42 4.8
Ratio
%
Ratio
%
437/458 410/458 430/458 417/458
95.4 89.5 93.9 91.0
20/46 39/46 24/46 39/46
43.5 84.8 52.2 84 8
5
6/18 33.3
Including ECP.HD. HD not subtyped according to RYE by the primary paihologists. Unclassifiable HD. (See table I).
The 72 cases of non-certain or questionable HD were subdivided as follows: 32/72 cases (44.4%) could not be classified due to insufficient histological or bioptic techniques. 23/72 or 2% of the total represent the borderline between HD and NHL, since the panel was unable to classify although good quality of biopsy and techniques permitted successful immunophenotyping. In 17/72 cases, the unclassifiability was caused by dissent among the observers (Table 1). The subtyping of HD according to Rye was confirmed in 680/1045 or 65% of HD cases accepted by the panel (Table 1). The switching in subtyping mainly concerns LD.HD and is followed by MC.HD and LP.HD. NS.HD was best (Table 2). Regarding LP.HD, only 25/37 (34.7%) of the primary diagnoses could be confirmed; the majority had to be switched to NS.HD or MC.HD, respectively. A consensus diagnosis after final classification could be achieved in 92.1% of all cases. 73 cases (6.4%) were dissent concerning the subtype of HD, and in 17 lymphoma cases (1.5%), the panel members could not agree whether to classify them as HD or NHL. The reproduction of grading NS HD in 2 groups according to the criteria of Bennett and MacLennan [4-6] revealed 84.5% grade I and 15,5% grade II NS.HD cases. Regarding only those 504 cases finally classified as NS I or II in which all panel members had initially diagnosed NS I or II, it can be shown that the percentage of those final NS I cases which had identically been clas-
Discussion The most important data of this panel classification of HD concerns the high amount of unclassifiable cases (19.3%). However, 7.3% have to be subtracted for insufficient techniques and could have been discarded before evaluation. Hence, these 7.3% demonstrate the reality presented by individual diagnosis to the hcmatooncology, since none of them was discussed by the primary pathologist critically, but classified as Hodgkin without further comment. There is a final dissent of a total of 8.1%, which has to be subdivided into 6.4% of minor dissent in subtyping, in part in distinguishing NS-1 and NS-2, leaving the remainder of major dissent at only 1.5%. This is of minor significant difference between 4 observers. The rest of the 23 unclassifiable cases may represent the grey zone between HD and NHL since all of them were presented by good quality of slides and could reliably be immunophenotyped and observers agreed in their unclassifiability. Critical reconsiderations of individual lymphoma typing are rare among current literature. British authors have presented an enormous impact by splitting the major compartment of disease, e.g. the large NS.HD group into two grades with distinct differences in its survival times amounting to roughly 20% within a 20year-period of retrospective observation [4—6]. It is of some interest therefore, to apply the British proposals to a prospective multicenter trial as performed in this material. However, the total number of NS.HD is only 57.3% in this trial compared to 71% in the British experience [4|. Moreover, the relation of NS-1 to NS-2 is 8.2 in these, versus 39.7 in the British results. The distribution of grade 1 NS.HD is 89% in our versus 60% of grade 1 in the British cases. These differences are caused by individual difficulties applying this classification successfully since the dissent of the individual compared to the consensus classification is striking (Table 3). Thus, one cannot expect convincing statisti-
Downloaded from http://annonc.oxfordjournals.org/ at Florida Atlantic University on February 3, 2015
LP.HD NS.HD MC.HD LD.HD UCHD' Others (codes 6-1 l) d
Primary diagnosis
Final Panel Classification NS II NS 1
33
cal differences in clinical outcome between the two grades by these results in our trial [1, 2]. Therefore, the prognostic relevance of this stimulating NS-grading system could not be confirmed by results from this trial as has been reported by others recently [10].
5.
6.
Acknowledgement
7.
Supported by grants from the Bundesminister fur Forschung und Technologie, Projekt-No. 012 P 550 A. 8.
References
10.
Correspondence to: Dr. J. Bernhards Patholog. Institut Medizinische Hochschule Hannover Konstanty-Gutschow-Str. 8 3000 Hannover 61, Germany
Downloaded from http://annonc.oxfordjournals.org/ at Florida Atlantic University on February 3, 2015
1. Diehl V, Pfreundschuh M, Loffler M et al. Studienprotokolle HD 4, HD 5, HD 6 der Deutschen Hodgkin-Studiengruppe. Kdln, 1988. 2. Loffler M, Pfreundschuh M, Hasenclever D et al. Prognostic risk factors in advanced Hodgkin's lymphoma. Report of the German Study Group. Blut 1988; 56: 273-81. 3. Wolf BC, Gilchrist KW, Mann RB et al. Evaluation of pathology review of malignant lymphomas and Hodgkin's disease in cooperative clinical trials. The Eastern Cooperative Oncology Group Experience. Cancer 1988; 62: 1301-5. 4. Bennett MH, MacLennan KA, Vaughan Hudson B et al. The clinical and prognostic relevance of histopathologic classifica-
9.
tion in Hodgkin's disease. Progress in Surg Pathol 1991; 10: 127-51. Bennett MH, MacLennan KA, Easterling MJ et al. The prognostic significance of cellular subtypes in nodular sclerosing Hodgkin's disease: an analysis of 271 non-laparotomised cases (BNLI Report No. 22). Clin Radiol 1983; 34:497-501. MacLennan MA, Bennett MH, Tu A et al. Relationship of histopathologic features to survival and relapse in nodular sclerosing Hodgkin's disease. Cancer 1989; 64: 1686-93. Kim H, Zeiman 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. Georgii A. New concepts on histopathology of Hodgkin's disease. Ann Oncol 1992; 3 (suppl. 4): S35-S38. Georgii A, Fischer R, Hiibner K et al. Histopathologische Klassifikation von Hodgkin-Lymphomen. Bericht der Referenzpathologie der Deutschen Hodgkin-Studie. Pathologe 1990; 11:322-6. Masih AS, Weisenburger DD, Vose JM et al. Histologic grade in nodular sclerosing Hodgkin's disease does not predict outcome. Lab Invest 1989; 60: 59A (347).
Original article Histopathological classification of Hodgkin's lymphomas Results from the reference pathology of the German Hodgkin Trial J. Bernhards,1 R. Fischer,2 K. Hiibner,3 E.-W. Schwarze4 & A. Georgii' 1
Patholog. Inst., Med. Hochschule Hannover, Kliniken Dortmund, Germany
2
Patholog. Inst., Universitdt Koln, -1 Patholog. Inst., Universitdt Frankfurt, * Patholog. Inst.,
Introduction The German Hodgkin Therapy Trial is a multicenter clinical trial evaluating the therapeutic effects of different radio- and chemotherapy in 3 separate stageoriented studies [1, 2]. Revisitation of diagnostic biopsies was considered to be an obligate part of trial design according to experiences described in the literature [3]. As interobserver disagreement is a well-known phenomenon in the diagnosis and classification of lymphomas [3], it was decided to establish a pathology panel instead of a single reference pathologist. Materials and methods Diagnostic biopsies of up to now 1,140 patients were obtained from the primary pathologists as paraffin blocks. Sections were performed and 4 were distributed to each pathologist. The 4 histopathologists of the panel have reviewed individual stainings from these sections and classified them individually according to the classification system and registered them by codes (Table 1). Dissent cases were revisited by workshop discussions on the microscope achieving a consensus diagnosis. Subtyping of nodular sclerosing (NS) Hodgkin's disease (HD) was achieved according to the criteria of Bennett and MacLennan |4-6).
Table I. System of final classification by a panel of 4 histopathologists from 1,140 cases primarily diagnosed as Hodgkin's disease by individuals from diagnostic biopsies. Code
System of classification
n
%
A. Hodgkin's Disease Clear subtypes 1 Lymphocytic Predominance LP.HD NS l.HD 2.1 Nodular Sclerosis Grade I NS 2.HD 2.2 Nodular Sclerosis Grade II MC.HD Mixed cellulanty 3 Lymphocytic depletion LD.HD 4 Epitheloid cell predominance ECP.HD Unclassifiable Hodgkin 6 Due to insufficient technique 7 Due to unusual features 10.1
Observer's dissent in subtyping
Total of A B. Unclassifiable Lymphomas 8.1 Due to insufficient technique 8.2 Due to unusual features 10.2 Dissent whether HD or NHL
31 588 72 159 8 39
2.7
51.6 6.3
13.9 0.7 3.4
51 24 73
4.5 2.1 6.4
1045
91.7
32 23 17
2.8 2.0 1.5
32 1
1.9 0.1
95
8.3
1140
100.0
C. No Hodgkin's Disease
Results Hodgkin's lymphoma (HD) could be confirmed in 1,045/1,140 cases (91.7%). Non-Hodgkin lymphomas (NHL) were revealed in 22 cases (1.9%), reconfirmed
9 11
Non-Hodgkin's Lymphoma (NHL) No malignancy
Total of B and C Total of all
Downloaded from http://annonc.oxfordjournals.org/ at Florida Atlantic University on February 3, 2015
Summary. Diagnostic biopsies of 1,140 previously untreated 13 HD of unclassifiable subtypes, 6.3 of not certain HD, 1.9 patients with Hodgkin's lymphoma from the German Non-Hodgkin Lymphoma, 1 case of non malignancy. GradHodgkin Therapy Trial were evaluated by a panel of 4 histo- ing of NS.HD into 2 subgroups according to the British claspathologists. Each case was classified by consensus of the sification differed conspicuously by 84.5% versus 15.5% and four according to an extended Rye-System including the 71.6% versus 28.4% in British results. This divergency is diversifying of NS.HD and the unclassifiable cases. The inter- explained by interobserver disagreement ranking from 43% observer agreement rate was 92.1% among the panel mem- to 85%. bers regarding the final classification. Primary Hodgkin diagnosis was approved in 91.7% (1045/1140 cases). The distribution of the 1,140 cases within this system was (in %) as Key words: Hodgkin's disease, histopathology, interobserver follows: 2.7 LP.HD, 57.9 NS.HD, 17.3 MC.HD, 0.7 LD.HD, disagreement
32
by markers. One single case (0.1%) provided no evidence of malignancy. In 73 cases (6.4%) the panel was unable to classify reliably or the panel members disagreed on individual classification after discussion, including phenotyping as well as clinical data (Table 1). Almost all cases of NHL were considered as peripheral T-cell lymphomas or large cell anaplastic lymphomas. Most of these had been diagnosed as MC.HD or LD.HD initially (Table 2).
sified by the individual panelist ranged from 95.4% (panelist 1) to 89.5% (panelist 2) whereas in NS II the range was from 84.8% (panelist 2) to 43.5% (panelist 1) (Table 3). Table 3. Interobserver agreement comparing the individual versus the final classification typing 504 NS.HD cases. Panelist
Table 2. Comparison of final panel classification to primary individual diagnosis. Panel classification
31 660 198 8 148
LP
NS
MC"
25 9
2 525 23 3 58
4 111 158
20
12
15
95
II Confirmed to primary subtype ratio 716/1140 25/72 % 62.8 34.7
525/631 83.2
LD
UCh
3 61
8 5 2 9
6
37
18
7
158/374 42 2
2/42 4.8
Ratio
%
Ratio
%
437/458 410/458 430/458 417/458
95.4 89.5 93.9 91.0
20/46 39/46 24/46 39/46
43.5 84.8 52.2 84 8
5
6/18 33.3
Including ECP.HD. HD not subtyped according to RYE by the primary paihologists. Unclassifiable HD. (See table I).
The 72 cases of non-certain or questionable HD were subdivided as follows: 32/72 cases (44.4%) could not be classified due to insufficient histological or bioptic techniques. 23/72 or 2% of the total represent the borderline between HD and NHL, since the panel was unable to classify although good quality of biopsy and techniques permitted successful immunophenotyping. In 17/72 cases, the unclassifiability was caused by dissent among the observers (Table 1). The subtyping of HD according to Rye was confirmed in 680/1045 or 65% of HD cases accepted by the panel (Table 1). The switching in subtyping mainly concerns LD.HD and is followed by MC.HD and LP.HD. NS.HD was best (Table 2). Regarding LP.HD, only 25/37 (34.7%) of the primary diagnoses could be confirmed; the majority had to be switched to NS.HD or MC.HD, respectively. A consensus diagnosis after final classification could be achieved in 92.1% of all cases. 73 cases (6.4%) were dissent concerning the subtype of HD, and in 17 lymphoma cases (1.5%), the panel members could not agree whether to classify them as HD or NHL. The reproduction of grading NS HD in 2 groups according to the criteria of Bennett and MacLennan [4-6] revealed 84.5% grade I and 15,5% grade II NS.HD cases. Regarding only those 504 cases finally classified as NS I or II in which all panel members had initially diagnosed NS I or II, it can be shown that the percentage of those final NS I cases which had identically been clas-
Discussion The most important data of this panel classification of HD concerns the high amount of unclassifiable cases (19.3%). However, 7.3% have to be subtracted for insufficient techniques and could have been discarded before evaluation. Hence, these 7.3% demonstrate the reality presented by individual diagnosis to the hcmatooncology, since none of them was discussed by the primary pathologist critically, but classified as Hodgkin without further comment. There is a final dissent of a total of 8.1%, which has to be subdivided into 6.4% of minor dissent in subtyping, in part in distinguishing NS-1 and NS-2, leaving the remainder of major dissent at only 1.5%. This is of minor significant difference between 4 observers. The rest of the 23 unclassifiable cases may represent the grey zone between HD and NHL since all of them were presented by good quality of slides and could reliably be immunophenotyped and observers agreed in their unclassifiability. Critical reconsiderations of individual lymphoma typing are rare among current literature. British authors have presented an enormous impact by splitting the major compartment of disease, e.g. the large NS.HD group into two grades with distinct differences in its survival times amounting to roughly 20% within a 20year-period of retrospective observation [4—6]. It is of some interest therefore, to apply the British proposals to a prospective multicenter trial as performed in this material. However, the total number of NS.HD is only 57.3% in this trial compared to 71% in the British experience [4|. Moreover, the relation of NS-1 to NS-2 is 8.2 in these, versus 39.7 in the British results. The distribution of grade 1 NS.HD is 89% in our versus 60% of grade 1 in the British cases. These differences are caused by individual difficulties applying this classification successfully since the dissent of the individual compared to the consensus classification is striking (Table 3). Thus, one cannot expect convincing statisti-
Downloaded from http://annonc.oxfordjournals.org/ at Florida Atlantic University on February 3, 2015
LP.HD NS.HD MC.HD LD.HD UCHD' Others (codes 6-1 l) d
Primary diagnosis
Final Panel Classification NS II NS 1
33
cal differences in clinical outcome between the two grades by these results in our trial [1, 2]. Therefore, the prognostic relevance of this stimulating NS-grading system could not be confirmed by results from this trial as has been reported by others recently [10].
5.
6.
Acknowledgement
7.
Supported by grants from the Bundesminister fur Forschung und Technologie, Projekt-No. 012 P 550 A. 8.
References
10.
Correspondence to: Dr. J. Bernhards Patholog. Institut Medizinische Hochschule Hannover Konstanty-Gutschow-Str. 8 3000 Hannover 61, Germany
Downloaded from http://annonc.oxfordjournals.org/ at Florida Atlantic University on February 3, 2015
1. Diehl V, Pfreundschuh M, Loffler M et al. Studienprotokolle HD 4, HD 5, HD 6 der Deutschen Hodgkin-Studiengruppe. Kdln, 1988. 2. Loffler M, Pfreundschuh M, Hasenclever D et al. Prognostic risk factors in advanced Hodgkin's lymphoma. Report of the German Study Group. Blut 1988; 56: 273-81. 3. Wolf BC, Gilchrist KW, Mann RB et al. Evaluation of pathology review of malignant lymphomas and Hodgkin's disease in cooperative clinical trials. The Eastern Cooperative Oncology Group Experience. Cancer 1988; 62: 1301-5. 4. Bennett MH, MacLennan KA, Vaughan Hudson B et al. The clinical and prognostic relevance of histopathologic classifica-
9.
tion in Hodgkin's disease. Progress in Surg Pathol 1991; 10: 127-51. Bennett MH, MacLennan KA, Easterling MJ et al. The prognostic significance of cellular subtypes in nodular sclerosing Hodgkin's disease: an analysis of 271 non-laparotomised cases (BNLI Report No. 22). Clin Radiol 1983; 34:497-501. MacLennan MA, Bennett MH, Tu A et al. Relationship of histopathologic features to survival and relapse in nodular sclerosing Hodgkin's disease. Cancer 1989; 64: 1686-93. Kim H, Zeiman 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. Georgii A. New concepts on histopathology of Hodgkin's disease. Ann Oncol 1992; 3 (suppl. 4): S35-S38. Georgii A, Fischer R, Hiibner K et al. Histopathologische Klassifikation von Hodgkin-Lymphomen. Bericht der Referenzpathologie der Deutschen Hodgkin-Studie. Pathologe 1990; 11:322-6. Masih AS, Weisenburger DD, Vose JM et al. Histologic grade in nodular sclerosing Hodgkin's disease does not predict outcome. Lab Invest 1989; 60: 59A (347).