Bone Marrow Involvement by Non-Hodgkin's Lymphoma: The Clinical Significance of Morphologic Discordance Between the Lymph Node and Bone Marrow By Maureen G. Conlan, Martin Bast, James O. Armitage, and Dennis D. Weisenburger for the Nebraska Lymphoma Study Group Bone marrow specimens from 317 patients with non-Hodgkin's lymphoma (NHL) obtained at initial staging were evaluated for the presence of lymphoma or benign lymphoid aggregates. Thirty-two percent (102 patients) had lymphoma in their bone marrow, and 9% had benign lymphoid aggregates. Bone marrow lymphoma was present in 39% of low-grade, 36% of intermediate-grade, and 18% of high-grade lymphomas. The bone marrow was involved in 25% of patients with diffuse large-cell or immunoblastic NHL (ie, diffuse histiocytic lymphoma of Rappaport). Bone marrow involvement did not affect survival of patients with low-grade NHL, but survival was significantly shorter (P = .03) for patients with intermediateand high-grade NHL with bone marrow involvement. Bone marrow involvement was equally common in B-cell and T-cell NHL (31% v 32%). However, patients with T-cell NHL and bone marrow involvement had shorter survival than B-cell NHL with marrow involve-
BONE
ment (P = .02) or T-cell NHL without marrow involvement (P= .05). A high incidence of morphologic discordance between lymph node and bone marrow was observed (ie, 40%), always with a more aggressive subtype in the lymph node than in the bone marrow. Presence of large-cell lymphoma in the bone marrow predicted for short survival. Survival for patients with small-cell lymphoma in their bone marrow did not differ significantly from patients with negative bone marrows. We conclude that bone marrow involvement in large-cell NHL, especially in those of T-cell origin, portends a poor prognosis. However, the subgroup of patients with an aggressive histologic subtype of NHL in a lymph node biopsy and small-cell NHL in the bone marrow do not have a poorer outlook than those without bone marrow involvement. J Clin Oncol 8: 1163-1172. © 1990 by American Society of ClinicalOncology.
MARROW involvement in the nonHodgkin's lymphomas (NHLs) may be of prognostic significance, and bone marrow biopsy is generally included in the initial staging of these patients. Since the introduction of the Rappaport system for classification of NHL,' there have been numerous reports on the incidence of bone marrow involvement with lymphoma.2-9 Similar studies have used the Lukes-Collins classification,1 0',1 which takes immunophenotype into
modified Working Formulation and immunophenotype analysis to study the incidence, pattern, and clinical significance of bone marrow involvement by NHL at the time of diagnosis. We also attempted to classify the histologic type of the lymphomatous infiltrate in the marrow and to compare it with the lymph node to determine if discordance is of any prognostic significance.
account, and the Kiel classification,12-14 a system unfamiliar to most American physicians. We have used the Working Formulation' 5 to classify bone marrow involvement by NHL. Reports have emphasized the dissimilar rates and patterns of involvement' 2 ,13,16" 20 by low-grade and intermediate- and high-grade lymphoma. Three recent studies have commented on the presence of discordant histologic appearance in the lymph node and bone marrow biopsies'""14, 2 1 and suggested that this may be of clinical significance. Since most pathologists merely report the bone marrow as positive or negative for lymphoma, it is of some importance to determine if this discordance has prognostic significance. We used the
Between July 1982 and February 1988, 317 patients were entered onto chemotherapy protocols of the Nebraska Lymphoma Study Group (a group of oncologists and hematologists in Nebraska, SD, and western IA with its headquarters at the University of Nebraska Medical Center) for the diagnosis of NHL. Patients were excluded from study if blood
MATERIALS AND METHODS
From the Departments of Internal Medicine, and Pathology and Microbiology, University of Nebraska Medical Center,Omaha,NE. Submitted August 31, 1989; accepted February23, 1990. Address reprint requests to Maureen G. Conlan, MD, Section of Hematology-Oncology,University of Texas Health Science Center at Houston, Medical School, PO Box 20708, Houston, TX77225. © 1990 by American Society of Clinical Oncology. 0732-183X/90/0807-0007$3.00/0
Journalof Clinical Oncology, Vol 8, No 7 (July), 1990: pp 1163-1172
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CONLAN ET AL
and bone marrow disease were indistinguishable from chronic lymphocytic leukemia. Patients were staged according to the Ann Arbor system.22 Routine evaluation included a complete history and physical examination, routine chemistries, complete blood count, chest roentgenogram, and, in most instances, computed tomographic (CT) scans of chest and abdomen and bone marrow aspirate and biopsy. All pathologic material was reviewed by one of us (DDW) at the time of diagnosis and the lymphoma was classified according to the Working Formulation," modified to recognize the subgroup of diffuse intermediate NHL. 23 The comparatively low incidence of low-grade lymphoma that we observed in this study is in keeping with our previous experience in Nebraska.24 Composite lymphomas were defined as those in which two or more distinct areas of NHL of different histology could be appreciated in a single lymph node; discordant lymphomas were defined as those in which such findings occur in separate anatomic disease sites.2 5 All bone marrows evaluated in this study were performed at the time of initial staging. Fifty-four patients had low-grade lymphoma, 180 intermediate-grade, and 76 high-grade. Ninety percent of the high-grade lymphomas were immunoblastic. Seven lymphomas could not be classified. Immunophenotype was determined as described previously2 6 in 221 cases. All low-grade lymphomas that were immunophenotyped had B-cell markers. Eighty-six percent of the intermediate- and high-grade lymphomas were typemarked as B-cell lymphomas and 14% marked as T-cell lymphomas. The majority of patients had stage III or IV disease (Table 1). They ranged in age from 15 to 90 years with a median age of 65 years. Forty-seven patients with low-grade lymphomas, 35 patients with intermediate- and high-grade lymphoma, and four unclassified lymphomas were treated with chloram2 bucil 12 mg/m orally days 1 through 5, vincristine I mg/m2 intravenously (IV) day 1, and prednisone 100 mg total dose orally days 1 through 5, at 3- to 4-week intervals. Two hundred twenty-one patients with intermediate- and highgrade lymphoma, seven patients with low-grade lymphoma, and three unclassified lymphomas were treated with cyclophos2 phamide 550 mg/m2 IV day 1, doxorubicin 50 mg/m IV day 2 1, procarbazine 100 mg/m orally days 1 through 7, bleomycin 10 mg/m2 subcutaneously (SQ) day 15, vincristine 1.4 mg/m 2 IV day 15, and prednisone 100 mg total dose orally 27 days 15 through 21 (CAPBOP) at 3- to 4-week intervals. Chemotherapy was continued until complete remission plus two more cycles or up to a maximum of seven cycles. Bone marrow aspirates, clot sections, and/or trephine biopsies were performed in the majority of these cases. Since Table 1. Stage of Lymphoma at Diagnosis Stage (%) II
Grade Low Intermediate High
III
IV
Total
5(9.3) 10(18.5) 10(18.5) 29(53.7) 54 16 (8.9) 30 (16.7) 31 (17.2) 103 (57.2) 180 5(6.6) 21 (27.6) 13 (17.1) 37(48.7) 76
Immunophenotype 13(6.6) 31 (15.8) 39(19.9) 113(57.7) 196 B 14(56) 25 2(8.0) 6(24) 3(12) T
these were performed at a number of hospitals, they were not processed uniformly, but all biopsies and clot sections were paraffin-embedded and the majority were stained with hematoxylin and eosin. Occasional biopsies and clot sections and all aspirate smears were stained with Wright-Giemsa stain. All bone marrow biopsies and clot sections were reviewed by one of the authors (DDW). One hundred thirty-one bone marrow specimens found to be positive for lymphoma or containing benign lymphoid aggregates or nodules were reevaluated for this study. Criteria used for diagnosis of benign lymphoid aggregates'98,29 were small well-delineated collections of mature-appearing lymphocytes with intermixed histiocytes, plasma cells, mast cells, and eosinophils at the periphery, small vessels transgressing the nodule, and usually interstitial in location. When lymphomatous involvement was judged to be present, biopsy sections were evaluated for degree and pattern of involvement. The following three patterns of lymphomatous involvement were defined: focal, diffuse, and mixed. Distribution of the lymphomatous infiltrate was noted to be paratrabecular, intertrabecular, or mixed (both paratrabecular and intertrabecular). Extent of involvement was categorized as less than 30% replacement of the bone marrow section by lymphoma, 30% to 70% replacement, and greater than 70% replacement. Prominent vascularity and fibrosis were noted, when present. The lymphoma cells in trephine biopsy or clot section were classified according to the predominant cell size into large-cell, mixed largeand small-cell, and small-cell. Patients with "pure" large-cell or mixed large- and small-cell were analyzed together for survival analyses. Actuarial survival probability curves were plotted according to the method of Kaplan and Meier.s3 Different curves were statistically compared using the log-rank test." RESULTS
As classified according to the Working Formulation, there were 54 cases (17%) of low-grade, 180 cases (57%) of intermediate-grade, and 76 cases (24%) of high-grade lymphoma (Table 2). There were 27 composite lymphomas that were classified according to the component with the highest grade (27 intermediate, one high). Seven lymphomas could not be further classified. Of 221 cases that were immunophenotyped, 196 (89%) were B-cell lymphomas and 25 (11%) were T-cell lymphomas. Benign lymphoid aggregates were detected in 28 bone marrow biopsies or clot sections, an incidence of 9% (Table 3). They appeared to be equally common in men and women (13 v 15). The median age of patients with benign lymphoid aggregates was 70 years (range, 46 to 83 years). Benign,lymphoid aggregates were slightly more common in patients with intermediate- and high-grade lymphoma than in those with lymphoma of low grade (9% v 6%). Benign lymphoid
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1165
BONE MARROW INVOLVEMENT BY NHL Table 2. Lymphoma Classification by Lymph Node Histology and Incidence of Bone Marrow Involvement at Diagnosis Bone Marrow Involvement (%)
Lymph Node Histology
N (%)
Low-grade Small lymphocytic Follicular small-cleaved Follicular mixed Mantle zone
54(17) 18(5.7) 13(4.1) 22 (7.0) 1(0.3)
21(38.9)
180 (56.8) 27 (8.5) 15(4.7) 10(3.2) 24(7.6) 78 (24.7) 26(8.2)
64 (35.5)
76(24.0) 69(21.9) 1(0.3) 5 (1.6) 1(1.3)
14(18.4) 12(17.4) 1(100) 1 (20) 0 (0)
Intermediate-grade Follicular large-cell Diffuse intermediate Diffuse small-cleaved Diffuse mixed Diffuse large-cell Composite High-grade Immunoblastic Lymphoblastic Small-noncleaved Composite Not otherwise classifiable Total
7(2.2) 317
8(44.4) 4(30.8) 8 (36.4) 1(100)
9 (33.3) 11 (73.3) 4(40) 8 (33.3) 24 (30.8) 8 (30.8)
4(57) 102 (32.2)
NOTE. Includes positive trephine biopsy, clot section, and/or marrow aspirate smear.
aggregates were present in only one case of T-cell lymphoma. One hundred two patients (32%) had bone marrow involvement at diagnosis. Of these patients, 99% (101 of 102) had at least one trephine biopsy (23% had bilateral biopsies), 78% (80 of 102) had clot sections, and 82% (85 of 102) had bone marrow aspirate smears available for review. It is not known how many patients with negative bone marrows underwent these studies, but one would assume similar numbers. The trephine biopsy was positive in 96 patients (30%), the clot section alone was positive in an additional four patients, and only the aspirate smear was positive in two patients. The trephine biopsy was the only positive bone marrow specimen in 29 patients. One patient with follicular large-cell lymphoma had peripheral blood involvement, but lymphoma could not be definitively diagnosed in the bone marrow specimens available. In those patients with bone marrow involvement, the sensitivity for a positive trephine biopsy was 94% (96 of 102), for clot section 65% (52 of 80), and for aspirate smear 46% (39 of 85). Of the 96 patients with positive trephine biopsies, 48 (50%) also had positive clot sections, and 37 (38%) also had positive aspirate smears.
The frequency of bone marrow involvement at diagnosis varied with the grade of NHL in the node (Table 2). Bone marrow involvement by lymphoma was present in 39% of low-grade, 33% of intermediate-grade, and 18% of high-grade lymphomas. Thirty-one percent (61 of 196) of all B-cell lymphomas, 29% (48 of 163) of the intermediate- and high-grade B-cell lymphomas, and 32% (eight of 25) of T-cell lymphomas (all intermediate- and high-grade) had bone marrow involvement. Less than 30% of the bone marrow was replaced by lymphoma in 49 patients (51%), 30% to 70% in 19 (20%), and greater than 70% in 28 (29%) (Table 4). This distribution, with the majority of patients having less than 30% of their marrow replaced by lymphoma, remained fairly constant for all histologies. Involvement of the marrow in T-cell lymphoma tended to be more extensive than in B-cell lymphoma: 88% of the patients had greater than 30% involvement compared with 43% for B-cell lymphoma. The pattern of involvement was focal in 60 patients (63%), diffuse in 30 (32%), and mixed in five (5%). This distribution also remained fairly constant for all histologies. However, T-cell lymphomas had more diffuse or mixed involvement, and B-cell lymphomas had more focal involvement. The lymphomatous infiltrate was paratrabecular in location in 26 patients (28%) and intertrabecular in 25 (27%), and infiltrates were both paraand intertrabecular in 43 patients (46%), often in association with a packed marrow. This pattern remained constant for most histologies; however, the high-grade lymphomas tended to have more intertrabecular infiltrates. T- and B-cell lymphomas had a similar distribution. Increased vascuTable 3. Results in 28 Patients With Benign Lymphoid Aggregates Characteristic
Result
Male:female Age Range Median Overall incidence Incidence in low-grade NHL Incidence in intermediate- and highgrade NHL Incidence in unclassified NHL Incidence in B-cell NHL Incidence in T-cell NHL
13:15
%
46-83 years 70 years 28/317 3/54
8.8 5.5
24/256 1/7 24/196 1/25
9.4 14.3 12.2 4
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1166
CONLAN ET AL Table 4. Extent and Pattern of Bone Marrow Involvement by Lymphoma at Diagnosis
Lymph Node Histology
Number With Bone Marrow Involvement*
Pattern of Bone Marrow Involvement (%)
Extent of Bone Marrow Involvement (%) < 30%
30%-70%
> 70%
Focal
19(19.8) 28(29)
60(63)
Diffuse
Mixed
Location of Bone Marrow Involvement (%) ParaIntertrabecular trabecular Mixed
Total
96
49(51)
30(31.5) 5(5.3)
26(27.6) 25(26.6) 43 (45.7)
Low-grade Intermediate-grade High-grade
21 57 14
12(57) 4 (19) 5 (24) 14(66.6) 6(28.6) 1(4.8) 27(47.4) 13(22.8) 18(31.6) 36(63.2) 17(29.8) 3(5.3) 7 (50) 4(28.6) 3(21.4) 8(57.1) 5(35.7) 1 (7.1)
7(33.3) 5(23.8) 9(42.9) 17(29.8) 13(22.8) 25(43.8) 1(7.1) 7 (50) 6 (42.9)
Small lymphocytic Small-cleaved, follicular, and diffuse Diffuse small irregular lymphocytic Mixed, follicular, and diffuse Large-cell, follicular and diffuse Immunoblastic Composite lymphoma
8
3(37.5)
1 (12.5)
4(50)
4(50)
4(50)
8
5(62.5)
1 (12.5)
2 (25)
5 (62.5)
9 14
4(44.4) 6(42.9)
4(44.4) 6(42.9)
1 (11.1) 2(14.2)
7(77.7) 9(64.3)
30 12 8
13(43.3) 7(58.3) 7(87.5)
5 (16.6) 2(16.6) 0(0)
12(40) 17(56.6) 12(40) 1 (3.3) 3(25) 7(58.3) 4(33.3) 1 (8.3) 1 (12.5) 7(87.5) 1 (12.5) 0(0)
B-cell
61
35(57.4)
10(16.4)
16(26.2) 45(73.8) 15(24.6) 1(1.6)
T-cell
8
1(12.5)
4(50)
3(37.5)
3(37.5)
0(0)
2 (25)
2 (25)
4 (50)
3 (37.5) 0(0)
3(37.5)
2 (25)
3 (37.5)
0(0) 1 (11.1) 3(21.4) 2(14.2)
3(33.3) 6(42.9)
1 (11.1) 4(28.6)
4(44.4) 4(28.6)
9 (30) 1 (8.3) 1(12.5)
6 (20) 14(46.6) 6 (50) 5 (41.7) 3(37.5) 4(50)
3(37.5) 2(25)
17(27.9) 15(24.6) 29(47.5) 3(37.5)
3(37.5)
2(25)
*Includes only those with positive trephine biopsy.
larity was detected in only six patients. Prominent fibrosis was present in three patients with diffuse large-cell lymphoma, diffuse mixed lymphoma, and composite lymphoma. Discordant histologic appearance between lymph node and bone marrow was observed in 41 patients (40% of those with positive bone marrows) (Table 5). In 41 of the 42 cases, it involved the presence of a high- or intermediate-grade lymphoma in the lymph node and a different intermediate (ie, less aggressive) or low-grade lymphoma in the bone marrow. The exception was a follicular mixed lymphoma in lymph node and large-cell lymphoma in bone marrow. In all other cases of low-grade lymphoma in the lymph node, the bone marrow also contained low-grade lymphoma. If only those patients with complete discordance between lymph node and bone marrow (ie, large-cell lymphoma at one site and small-cell lymphoma at the other site) are considered, the incidence of discordance is only 21% (21 of 102) and occurred only in the setting of large-cell or immunoblastic lymphoma in the lymph node. Of the lymphomas that were immunophenotyped and had bone marrow involvement, 52% of the B-cell lymphomas and 38% of the T-cell lymphomas showed discordant histology between lymph node and bone marrow; this represents 16% of all the B-cell lymphomas and
12% of all the T-cell lymphomas. When only the intermediate- and high-grade lymphomas were considered, discordant histology was present in 46% (22 of 48) of the B-cell lymphomas and 25% (two of eight) of the T-cell lymphomas (P = NS). Pattern, extent, and location of bone marrow involvement were similar for lymphomas with and without discordance when immunophenotype and only the pure nodal large-cell versus marrow small-cell histology were considered. For B-cell lymphomas with histologic discordance, marrow involvement tended to be minimal: 68% (13 of 19) had less than 30% marrow involvement (compared with 57% for all B-cell lymphomas with marrow involvement). The involvement was focal in 79% (compared with 74%) and paratrabecular in 53%. The T-cell lymphomas with discordant histology all had extensive marrow involvement (> 50%). When all histologic subtypes were included, patients with bone marrow involvement had a worse prognosis, as determined by actuarial survival, than those without marrow involvement (P = .02, Fig 1). However, patients with lowgrade lymphoma and bone marrow involvement fared no worse than those without marrow involvement. Patients with intermediate- and highgrade lymphomas and marrow involvement had a shorter survival than those without marrow
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1167
BONE MARROW INVOLVEMENT BY NHL Table 5. Comparison of Lymph Node and Bone Marrow Lymphoma Number with Positive Bone Marrow
Lymph Node Histology Large-cell and immunoblostic
43
Mixed Follicular
14 8
Bone Marrow Histology
No.
%
Large-cell Mixed Small-cell Composite
10 10 21 2
23 23 49 5
6
Diffuse
Small-cell (small lymphocytic, intermediate or small-cleaved)
26
Large-cell Mixed Small-cell Large-cell Mixed Small-cell
1 2 5 1 2 3
Small-Cell
26
12.5 25 62.5 17 33 50
100
NOTE. Includes only those with positive trephine biopsy. Excludes those with node histology of composite lymphoma (N = 8), lymphoblastic lymphoma (N = 1), small-noncleaved lymphoma (N = 1), and not otherwise classifiable (N = 4).
involvement (P = .03). When intermediate- or high-grade lymphomas were analyzed separately, bone marrow involvement did not significantly affect survival for the intermediate-grade lymphomas (P = .13) but high-grade lymphomas with marrow involvement had a much worse prognosis than those without marrow involvement (P = .007). Those patients with intermediate- and highgrade lymphomas with large-cell lymphoma in their bone marrow had a worse prognosis than those with small-cell lymphoma in their marrow (P = .05, Fig 2). Survival was significantly worse for patients with large-cell lymphoma in their marrow compared with those without marrow involvement (P = .03, Fig 2). However, survival was similar for patients with small-cell lymphoma in the marrow and those without marrow involvement. Similar results were found when
only intermediate-grade lymphomas were considered in the analysis. Survival was similar for all patients with B-cell or T-cell lymphomas. However, patients with stage IV B-cell NHL survived longer than those with stage IV T-cell NHL (P = .03), and when only patients with marrow involvement were compared, patients with T-cell lymphoma had significantly shorter survival (P = .02, Fig 3). This difference persisted when only those patients with intermediate- and high-grade NHL were included (P = .05). When B-cell lymphomas were analyzed independently, bone marrow involvement did not significantly affect survival, even when low-grade lymphomas were excluded. However, bone marrow involvement in T-cell lymphoma resulted in shorter survival com0)t
1-
C
0.8C
0.6-
.2_ .c
0.6-
Bone Marrow Negative
2 0.-
0
cl
Marrow Negative
0.4Small Cell in Marrow
0.2-
0
BoneMarrow -Posive Bone Marrow Positive
a0 0.2-0.
0S25
S
75
Survival in Months
Fig 1. Survival of all 317 patients based on the results of bone marrow examination. Patients without bone marrow involvement had a superior survival (P = .02).
L
Large Cell in Marrow
00
10
20
30
40
50
60
70
Survival in Months
Fig 2. Survival of patients with intermediate- and highgrade NHL based on presence and type of marrow involvement. Patients with large-cell NHL in the marrow have a worse prognosis than those with negative marrows (P = .02) and those with small-cell lymphoma in the marrow (P = .05).
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1168 0n
CONLAN ET AL
10.8-
C
rr CO
2 0
0.6-
BT-Cell NHL
0.4-
a
0.2-
2 a.
0-
T-Cell NHL ,
0
10
20
30 ,
,
40
50
60
,
70
Survival in Months Fig 3. Patients with B-cell NHL with marrow involvement survived longer than similar patients with T-cell NHL
(P = .02).
pared with those without marrow involvement (P = .05).
The presence of benign lymphoid aggregates in the bone marrow did not affect survival. This was true both for the low-grade lymphomas as well as for the intermediate- and high-grade lymphomas. Survival was similar for all patients regardless of extent of replacement of the bone marrow by lymphoma when all histologies were considered together. No significant differences in survival were observed when low-grade lymphomas were analyzed alone; however, the numbers were small. When intermediate- and high-grade lymphomas were analyzed as a group, survival was significantly different for those with greater than 70% marrow replacement compared with those with less than 30% marrow replacement by lymphoma (P = .03). No survival differences were observed between the group with 30% to 70% replacement and the other two groups. Pattern of involvement was also of prognostic significance for the intermediate- and high-grade lymphomas. Patients with focal involvement survived longer than those with diffuse involvement (P = .02). However, location of infiltrate (paratrabecular v intertrabecular) had no impact on survival. DISCUSSION
Using the Working Formulation, we found an overall incidence of bone marrow involvement with lymphoma at time of diagnosis of 32%. As emphasized by other investigators,2,3,5,8,10,11 we found the trephine biopsy produced a higher yield than either clot section or aspirate smear. The trephine biopsy failed to detect marrow involvement that was noted on clot section or aspirate smear in only six patients (2%).
We found a fairly uniform frequency of marrow involvement by NHL for both low and intermediate histologies (39% and 36%, respectively) and a low frequency of involvement in the high-grade lymphomas (18%). Some previous studies, using the Rappaport classification, have reported a higher incidence of marrow involvement in the low-grade lymphomas usually in the range of 50% to 60%,4,5,7,'1011.18 but others have reported an incidence closer to our own.2,8,9,16,19
In interpreting our data on low-grade lymphomas, it must be pointed out that our study only included those patients treated with combination chemotherapy; therefore, patients who may have been treated with radiation therapy, noncombination chemotherapy, or observation were excluded. Previous investigators have generally found a lower incidence of marrow involvement in the large-cell histology (histiocytic lymphoma of Rappaport), in the range of 10% to 20%,2,4,5,7,16,18,20'32,33
compared with our observed
frequency of 31% for diffuse and 33% for follicular large-cell lymphoma. If immunoblastic lymphoma is included with the intermediate lymphomas, as may have been the case in past studies, an incidence of bone marrow involvement of 25% is obtained, closer to that reported in the literature. There are no previous reports that comment on bone marrow involvement in the high-grade lymphomas other than for diffuse undifferentiated (small noncleaved) lymphoma, in which there has been a wide range of 0% to 67% reported.4 '8' 16' 18'19 Only one of our five patients with this diagnosis had marrow involvement. As has been previously reported,2 3 the diffuse small irregular lymphocytic (ie, diffuse intermediate) lymphomas had a very high incidence of marrow involvement (73%). The presence of marrow involvement by lymphoma was of no prognostic significance for patients with low-grade lymphomas. This was true when patients with stage IV disease with marrow involvement were compared with stage III patients or with stage IV patients without marrow involvement. This confirms the observation noted by Bennett et a134 and suggests that bone marrow biopsy may be of no value in the staging of patients with stage III low-grade lymphoma. As noted by others,32-34 we found that bone marrow involvement by lymphoma in the intermediate- and high-grade lymphomas carries
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1169
BONE MARROW INVOLVEMENT BY NHL
a poor prognosis. In a univariate analysis, Fisher et a132 found bone marrow involvement to carry a worse prognosis than any other site of involvement. Armitage et a133 found that bone marrow involvement in diffuse histiocytic lymphoma carried a poor prognosis. However, in a multivariate analysis, Shipp et al" found that bone marrow involvement did not alter prognosis. The presence of bone marrow involvement in the intermediate- and high-grade lymphomas did not affect survival when compared with other stage IV patients without marrow involvement or to stage III patients. This finding does not support the report by Bennett et a134 that survival in stage IV patients with diffuse histiocytic and diffuse mixed lymphoma with marrow involvement is worse than in patients with stage III disease. However, we did include a more diverse group of patients than Bennett et al. They also noted similar survival for stage IV patients with or without marrow involvement. Considerable diversity has been noted in the degree and pattern of bone marrow involvement by lymphoma. Most patients with nodular poorly differentiated lymphocytic lymphoma have been reported to have focal infiltrates, frequently paratrabecular in location, and often replacing less than 30% of the bone marrow. 4 9 "-11Our patients with low-grade lymphoma also tended to have focal disease with less than 30% marrow involvement, but a paratrabecular location was not striking. Bone marrow involvement by intermediate- and high-grade lymphomas also tended to be focal with less than 30% marrow replacement and showed no predilection for a paratrabecular location. Others have reported significant diversity in bone marrow findings in large-cell lymphoma. 9 We found no difference in survival for patients with low-grade lymphoma for the various degrees and patterns of bone marrow infiltration. However, in the intermediate- and high-grade lymphomas, greater than 70% marrow replacement by lymphoma and a diffuse pattern of involvement were associated with a worse prognosis. Location of infiltrates did not correlate with survival. Foucar et al' 0o,1 have reported on the degree and pattern of marrow involvement in B- and T-cell lymphomas. They found B-cell lymphomas tended to be focal and paratrabecular in location with less than 30% marrow replacement,
whereas T-cell lymphomas tended to be nonparatrabecular or diffuse but also tended to replace less than 30% of the marrow. Hanson et a136 reported similar results but with a slightly higher degree of marrow replacement. They also noted a high incidence of polycellular reactive infiltrate, prominent vascularity, and necrosis. Our patients with T-cell lymphoma had both focal and diffuse marrow infiltration with an equal distribution between paratrabecular and nonparatrabecular location. We also noted that patients with T-cell lymphoma tended to have a higher degree of marrow infiltration than the B-cell group. The significance of discordant histologic subtypes of NHL between lymph node and other sites of involvement by lymphoma at diagnosis has been noted by Fisher et a137 and Mead et al. 25 When two subtypes with different prognoses are found at different sites, the prognosis may be intermediate. 37 Discordance has also been re11 14 21 25 ported for lymph node and bone marrow. ' , , Both large-cell lymphoma in lymph node with 11 14 24 small-cell lymphoma in bone marrow, , ,21, and small-cell lymphoma in lymph node with large-cell lymphoma in bone marrow 11' 14 have been reported. Jagannath et a12l in a study evaluating only patients with diffuse large-cell lymphoma found that 10 of 61 (16%) patients with large-cell lymphoma in lymph node biopsy also had large-cell lymphoma in their marrow, but 11 of 61 (18%) had small-cell lymphoma in their bone marrow. However, when only those patients with bone marrow lymphoma are considered in the analysis, 52% of patients had histologic discordance. Patients with large-cell lymphoma in their marrow had a worse prognosis (P = .01) than either patients with small-cell lymphoma in their marrow or a negative marrow. Bartl et a1' 4 also compared node histology to bone marrow histology and included all histologic subtypes. They found a 24% incidence of discordance, which included both lower grade and higher grade lymphoma in the marrow compared with lymph node. Fisher et al37 reported a 33% incidence of discordant histology when all histologies were considered and two or more positive biopsy sites were available for review. Eighteen percent were discordant in diffuse versus nodular pattern, and 15% were discordant in cellular type. Mead et a125 reported a much lower incidence of discordance: 9.3% overall, and 4.8%
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CONLAN ET AL
when comparing "favorable" to "unfavorable" histology. However, they do not report how many of these patients had at least two anatomic sites biopsied. Therefore, their figure may be falsely low. We found a 40% incidence of discordance between lymph node and bone marrow when considering only those patients with marrow lymphoma. However, this is reduced to 21% when only those patients with large-cell lymphoma in lymph node and small-cell lymphoma in bone marrow are included (ie, excluding "mixed" histology). Our inclusion of the mixed histology lymphomas as discordant if both sites were not mixed may therefore explain the high incidence of discordance that we observed, as may the differing ways in which discordance has been reported in the literature (Table 6). There was complete concordance for all but one lowgrade lymphoma. We found that patients with intermediate- and high-grade NHL and largecell lymphoma in the bone marrow had a worse prognosis than those with small-cell lymphoma in the bone marrow (P = .05), and that patients with small-cell lymphoma in the marrow do no worse than those with negative marrows. Although the discordant small-cell histology in the bone marrow was associated with minimal marrow involvement (< 30% in 68%, primarily focal), this was the pattern that was observed for the majority of bone marrow infiltrates. The small-cell histology was, however, more commonly associated with a paratrabecular location, suggesting a follicular center origin. For the aforementioned reasons and the lack of fulfillment of the criteria for benign lymphoid aggregates, we believe that these lymphoid infiltrates truly represented lymphomatous involvement of the marrow. In all cases but one, the discordance involved an intermediate- or high-grade lymphoma on lymph node biopsy and a low-grade or
intermediate-grade lymphoma in the bone marrow (Table 5). Two-hundred twenty-one patients with NHL in our study were immunophenotyped; 89% marked as B-cell lymphomas and 11% marked as T-cell lymphomas. All of the T-cell lymphomas were of intermediate- and high-grade. Bone marrow involvement was present in 31% of the B cell-lymphomas (29% of the intermediate- and high-grade) and 32% of the T-cell lymphomas. Foucar et a110'o11have reported a similar incidence of bone marrow involvement for B-cell lymphomas (51%) but a much higher incidence of marrow involvement for the T-cell lymphomas (65%). Hanson et al, 36 reporting from the same institution, found an 80% incidence of bone marrow involvement at diagnosis for T-cell lymphoma. However, Weisenburger et a138 reporting on 39 cases of T-cell lymphoma (some of which are included in this report), and Coiffier et al,39 reporting on 63 cases of T-cell lymphoma, found an incidence of marrow involvement of only 28% and 22%, respectively, more in agreement with our own findings. Similarly, Greer et al4° reported a 37% incidence of bone marrow involvement in T-cell lymphoma at diagnosis. Although a slightly higher incidence of discordant histology was observed for the intermediate- and high-grade lymphomas of B-cell immunophenotype than for the T-cell lymphomas, this was not statistically significant and does not explain the poorer prognosis associated with bone marrow involvement in the T-cell lymphomas. In conclusion, we have found that bone marrow biopsy in the low-grade lymphomas offers little information of prognostic significance but provides much useful information in the intermediate- and high-grade lymphomas. A high incidence of bone marrow involvement was found for the intermediate-grade lymphomas, and its pres-
Table 6. Incidence of Discordant Histology in the Literature Histologies Considered Diffuse large-cell All All All All Intermediate- and high-grade
Anatomic Sites Node v bone Node v bone > 2 Not reported Node v bone Node v bone
marrow marrow
marrow marrow
Discordance (%)
Reference
11/21 (52) 29/120 (24) 33/101 (33) 30/323 (9.3) 41/102 (40) 24/49 (49)
Jagannath et a121 Bartl et al4 Fisher et al" Mead et a125 Present series Present series
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BONE MARROW INVOLVEMENT BY NHL
ence correlated with decreased survival. In these patients, the distinction between large-cell and small-cell lymphoma in the marrow was important and proved to be prognostically significant. Bone marrow involvement in T-cell lymphomas
was associated with a poor prognosis, possibly due to the more extensive lymphomatous involvement seen with this immunophenotype. Thus, bone marrow biopsy remains a useful tool in the staging of patients with large-cell lymphoma.
APPENDIX Members of the Nebraska Lymphoma Study Group Who Participated in This Study University of Nebraska Medical Center
James O. Armitage, MD Philip J. Bierman, MD Douglas Harrington, MD James Linder, MD David Purtilo, MD Dennis D. Weisenburger, MD James A. Maillaird, MD P. Steven Johnson, MD David Gnarra, MD Herbert A. Hartman, MD Bernard Korbitz, MD Robert M. Langdon, MD David Silverberg, MD Gamini Soori, MD Vincent Bjorling, MD William M. Packard, MD John Casey, MD Monroe D. Dowling, MD Mark Hutchins, MD Timothy Judge, MD Daniel F. Moravec, MD W. Cary Peterson, MD Scot Sorensen, MD Warren Pevnik, MD David Howe, MD John Okerbloom, MD Robert Warner, MD Robert F. Thompson MD George K. Bascom, MD Thomas Buroker, DO Roscoe Morton, MD Robert Shreck, MD Mark Westberg, MD
Creighton University Omaha, NE
Scottsbluff, NE Lincoln, NE
North Platte, NE Hastings, NE Council Bluffs, IA Yankton, SD Kearney, NE Des Moines, IA
REFERENCES 1. Rappaport H: Tumors of the hematopoietic system, in Atlas of Tumor Pathology, section 3, fascicle 8. Washington, DC, Armed Forces Institute of Pathology, 1966 2. Jones SE, Rosenberg SA, Kaplan HS: Non-Hodgkin's lymphomas. I. Bone marrow involvement. Cancer 29:954960, 1972 3. Liao KT: The superiority of histologic sections of aspirated bone marrow in malignant lymphomas. A review of 1,124 examinations. Cancer 27:618-628, 1971 4. Dick F, Bloomfield CD, Brunning RD: Incidence, cytology, and histopathology of non-Hodgkin's lymphomas in the bone marrow. Cancer 33:1382-1398, 1974
5. McKenna RW, Bloomfield CD, Brunning RD: Nodular lymphoma: Bone marrow and blood manifestations. Cancer 36:428-440, 1975 6. Bloomfield CD, McKenna RW, Brunning RD: Significance of haematological parameters in the non-Hodgkin's malignant lymphomas. Br J Haematol 32:41-46, 1976 7. Stein RS, Ultmann JE, Byrne GE Jr, et al: Bone marrow involvement in non-Hodgkin's lymphoma. Implications for staging and therapy. Cancer 37:629-636, 1976 8. Dee JW, Valdivieso M, Drewinko B: Comparison of the efficacies of closed trephine needle biopsy, aspirated paraffinembedded clot section, and smear preparation in the diagno-
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embedded clot section, and smear preparation in the diagnosis of bone-marrow involvement by lymphoma. Am J Clin Pathol 65:183-194, 1976 9. Brunning RD, McKenna RW: Bone marrow manifestations of malignant lymphoma and lymphoma-like conditions. Pathology Annu 14:1-59, 1979 10. Foucar K, McKenna RW, Frizzera G, et al: Incidence and patterns of bone marrow and blood involvement by lymphoma in relationship to the Lukes-Collins classification. Blood 54:1417-1422, 1979 11. Foucar K, McKenna RW, Frizzera G, et al: Bone marrow and blood involvement by lymphoma in relationship to the Lukes-Collins classification. Cancer 49:888-897, 1982 12. Bartl R, Frisch B, Burkhardt R, et al: Assessment of bone marrow histology in the malignant lymphomas (nonHodgkin's): Correlation with clinical factors for diagnosis, prognosis, classification and staging. Br J Haematol 51:511 530, 1982 13. Bartl R, Frisch B, Burkhardt R, et al: Lymphoproliferations in the bone marrow: Identification and evolution; classification and staging. J Clin Pathol 37:233-254, 1984 14. Bartl R, Hansmann M-L, Frisch B, et al: Comparative histology of malignant lymphomas in lymph node and bone marrow. Br J Haematol 69:229-237, 1988 15. Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute-sponsored study of classifications of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49:2112-2135, 1982 16. Kim H, Dorfman RF: Morphological studies of 84 untreated patients subjected to laparotomy for the staging of non-Hodgkin's lymphomas. Cancer 33:657-674, 1974 17. Brunning RD, Bloomfield CD, McKenna RW, et al: Bilateral trephine bone marrow biopsies in lymphoma and other neoplastic diseases. Ann Intern Med 82:365-366, 1975 18. Chabner BA, Johnson RE, Young RC, et al: Sequential nonsurgical and surgical staging of non-Hodgkin's lymphoma. Ann Intern Med 85:149-154, 1976 19. McKelvey EM, Gottlieb JA, Wilson HE, et al: Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 38:1484-1493, 1976 20. Goffinet DR, Warnke R, Dunnick NR, et al: Clinical and surgical (laparotomy) evaluation of patients with nonHodgkin's lymphomas. Cancer Treat Rep 61:981-992, 1977 21. Jagannath S, Velasquez WS, Tucker SL, et al: Stage IV diffuse large-cell lymphoma: A long-term analysis. J Clin Oncol 3:39-47, 1985 22. Carbone PP, Kaplan HS, Musshoff L, et al: Report of the committee on Hodgkin's disease staging classification. Cancer Res 31:1860-1861, 1971 23. Weisenburger DD, Nathwani BN, Diamond LW, et al: Malignant lymphoma, intermediate lymphocytic type: A clinicopathologic study of 42 cases. Cancer 48:1415-1425, 1981
24. Harrington DS, Ye Y, Weisenburger DD, et al: Malignant lymphoma in Nebraska and Guangzhou, China: A comparative study. Hum Pathol 18:924-928, 1987 25. Mead GM, Kushlan P, O'Neil M, et al: Clinical aspects of non-Hodgkin's lymphomas presenting with discordant histologic subtypes. Cancer 52:1496-1501, 1983 26. Linder J, Ye Y, Harrington DS, et al: Monoclonal antibodies marking T lymphocytes in paraffin-embedded tissue. Am J Pathol 121:1-8, 1987 27. Armitage JO, Weisenburger DD, Hutchins M, et al: Chemotherapy for diffuse large-cell lymphoma-Rapidly responding patients have more durable remissions. J Clin Oncol 4:160-164, 1986 28. Maeda K, Hyun BH, Rebuck JW: Lymphoid follicles in bone marrow aspirates. Am J Clin Pathol 67:41-48, 1977 29. Navone R, Valpreda M, Pich A: Lymphoid nodules and nodular lymphoid hyperplasia in bone marrow biopsies. Acta Haematol 74:19-22, 1985 30. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:475-481, 1958 31. Peto R, Pike MC: Conservation of the approximation (O-E) 2E in the log-rank test for survival data on tumor incidence data. Biometrics 29:579-582, 1973 32. Fisher RI, DeVita VT, Johnson BL, et al: Prognostic factors for advanced diffuse histiocytic lymphoma following treatment with combination chemotherapy. Am J Med 63: 177-182, 1977 33. Armitage JO, Dick FR, Corder MP, et al: Predicting therapeutic outcome in patients with diffuse histiocytic lymphoma treated with cyclophosphamide, Adriamycin, vincristine and prednisone (CHOP). Cancer 50:1695-1702, 1982 34. Bennett JM, Cain KC, Glick JH, et al: The significance of bone marrow involvement in non-Hodgkin's lymphoma: The Eastern Cooperative Oncology Group experience. J Clin Oncol 4:1462-1469, 1986 35. Shipp MA, Harrington DP, Klatt MM, et al: Identification of major prognostic subgroups of patients with largecell lymphoma treated with m-BACOD or M-BACOD. Ann Intern Med 104:757-765, 1986 36. Hanson CA, Brunning RD, Gajl-Peczalska KJ, et al: Bone marrow manifestations of peripheral T-cell lymphoma. Am J Clin Pathol 86:449-460, 1986 37. Fisher RI, Jones RB, DeVita VT, et al: Natural history of malignant lymphomas with divergent histologies at staging evaluation. Cancer 47:2022-2025, 1981 38. Weisenburger DD, Linder J, Armitage JO: Peripheral T-cell lymphoma: A clinicopathologic study of 42 cases. Hematol Oncol 5:175-187, 1987 39. Coiffier B, Berger F, Bryon P-A, et al: T-cell lymphomas: Immunologic, histologic, clinical, and therapeutic analysis of 63 cases. J Clin Oncol 6:1584-1589, 1988 40. Greer JP, York JC, Cousar JB, et al: Peripheral T-cell lymphoma: A clinicopathologic study of 42 cases. J Clin Oncol 2:788-789, 1984
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BONE
ment (P = .02) or T-cell NHL without marrow involvement (P= .05). A high incidence of morphologic discordance between lymph node and bone marrow was observed (ie, 40%), always with a more aggressive subtype in the lymph node than in the bone marrow. Presence of large-cell lymphoma in the bone marrow predicted for short survival. Survival for patients with small-cell lymphoma in their bone marrow did not differ significantly from patients with negative bone marrows. We conclude that bone marrow involvement in large-cell NHL, especially in those of T-cell origin, portends a poor prognosis. However, the subgroup of patients with an aggressive histologic subtype of NHL in a lymph node biopsy and small-cell NHL in the bone marrow do not have a poorer outlook than those without bone marrow involvement. J Clin Oncol 8: 1163-1172. © 1990 by American Society of ClinicalOncology.
MARROW involvement in the nonHodgkin's lymphomas (NHLs) may be of prognostic significance, and bone marrow biopsy is generally included in the initial staging of these patients. Since the introduction of the Rappaport system for classification of NHL,' there have been numerous reports on the incidence of bone marrow involvement with lymphoma.2-9 Similar studies have used the Lukes-Collins classification,1 0',1 which takes immunophenotype into
modified Working Formulation and immunophenotype analysis to study the incidence, pattern, and clinical significance of bone marrow involvement by NHL at the time of diagnosis. We also attempted to classify the histologic type of the lymphomatous infiltrate in the marrow and to compare it with the lymph node to determine if discordance is of any prognostic significance.
account, and the Kiel classification,12-14 a system unfamiliar to most American physicians. We have used the Working Formulation' 5 to classify bone marrow involvement by NHL. Reports have emphasized the dissimilar rates and patterns of involvement' 2 ,13,16" 20 by low-grade and intermediate- and high-grade lymphoma. Three recent studies have commented on the presence of discordant histologic appearance in the lymph node and bone marrow biopsies'""14, 2 1 and suggested that this may be of clinical significance. Since most pathologists merely report the bone marrow as positive or negative for lymphoma, it is of some importance to determine if this discordance has prognostic significance. We used the
Between July 1982 and February 1988, 317 patients were entered onto chemotherapy protocols of the Nebraska Lymphoma Study Group (a group of oncologists and hematologists in Nebraska, SD, and western IA with its headquarters at the University of Nebraska Medical Center) for the diagnosis of NHL. Patients were excluded from study if blood
MATERIALS AND METHODS
From the Departments of Internal Medicine, and Pathology and Microbiology, University of Nebraska Medical Center,Omaha,NE. Submitted August 31, 1989; accepted February23, 1990. Address reprint requests to Maureen G. Conlan, MD, Section of Hematology-Oncology,University of Texas Health Science Center at Houston, Medical School, PO Box 20708, Houston, TX77225. © 1990 by American Society of Clinical Oncology. 0732-183X/90/0807-0007$3.00/0
Journalof Clinical Oncology, Vol 8, No 7 (July), 1990: pp 1163-1172
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and bone marrow disease were indistinguishable from chronic lymphocytic leukemia. Patients were staged according to the Ann Arbor system.22 Routine evaluation included a complete history and physical examination, routine chemistries, complete blood count, chest roentgenogram, and, in most instances, computed tomographic (CT) scans of chest and abdomen and bone marrow aspirate and biopsy. All pathologic material was reviewed by one of us (DDW) at the time of diagnosis and the lymphoma was classified according to the Working Formulation," modified to recognize the subgroup of diffuse intermediate NHL. 23 The comparatively low incidence of low-grade lymphoma that we observed in this study is in keeping with our previous experience in Nebraska.24 Composite lymphomas were defined as those in which two or more distinct areas of NHL of different histology could be appreciated in a single lymph node; discordant lymphomas were defined as those in which such findings occur in separate anatomic disease sites.2 5 All bone marrows evaluated in this study were performed at the time of initial staging. Fifty-four patients had low-grade lymphoma, 180 intermediate-grade, and 76 high-grade. Ninety percent of the high-grade lymphomas were immunoblastic. Seven lymphomas could not be classified. Immunophenotype was determined as described previously2 6 in 221 cases. All low-grade lymphomas that were immunophenotyped had B-cell markers. Eighty-six percent of the intermediate- and high-grade lymphomas were typemarked as B-cell lymphomas and 14% marked as T-cell lymphomas. The majority of patients had stage III or IV disease (Table 1). They ranged in age from 15 to 90 years with a median age of 65 years. Forty-seven patients with low-grade lymphomas, 35 patients with intermediate- and high-grade lymphoma, and four unclassified lymphomas were treated with chloram2 bucil 12 mg/m orally days 1 through 5, vincristine I mg/m2 intravenously (IV) day 1, and prednisone 100 mg total dose orally days 1 through 5, at 3- to 4-week intervals. Two hundred twenty-one patients with intermediate- and highgrade lymphoma, seven patients with low-grade lymphoma, and three unclassified lymphomas were treated with cyclophos2 phamide 550 mg/m2 IV day 1, doxorubicin 50 mg/m IV day 2 1, procarbazine 100 mg/m orally days 1 through 7, bleomycin 10 mg/m2 subcutaneously (SQ) day 15, vincristine 1.4 mg/m 2 IV day 15, and prednisone 100 mg total dose orally 27 days 15 through 21 (CAPBOP) at 3- to 4-week intervals. Chemotherapy was continued until complete remission plus two more cycles or up to a maximum of seven cycles. Bone marrow aspirates, clot sections, and/or trephine biopsies were performed in the majority of these cases. Since Table 1. Stage of Lymphoma at Diagnosis Stage (%) II
Grade Low Intermediate High
III
IV
Total
5(9.3) 10(18.5) 10(18.5) 29(53.7) 54 16 (8.9) 30 (16.7) 31 (17.2) 103 (57.2) 180 5(6.6) 21 (27.6) 13 (17.1) 37(48.7) 76
Immunophenotype 13(6.6) 31 (15.8) 39(19.9) 113(57.7) 196 B 14(56) 25 2(8.0) 6(24) 3(12) T
these were performed at a number of hospitals, they were not processed uniformly, but all biopsies and clot sections were paraffin-embedded and the majority were stained with hematoxylin and eosin. Occasional biopsies and clot sections and all aspirate smears were stained with Wright-Giemsa stain. All bone marrow biopsies and clot sections were reviewed by one of the authors (DDW). One hundred thirty-one bone marrow specimens found to be positive for lymphoma or containing benign lymphoid aggregates or nodules were reevaluated for this study. Criteria used for diagnosis of benign lymphoid aggregates'98,29 were small well-delineated collections of mature-appearing lymphocytes with intermixed histiocytes, plasma cells, mast cells, and eosinophils at the periphery, small vessels transgressing the nodule, and usually interstitial in location. When lymphomatous involvement was judged to be present, biopsy sections were evaluated for degree and pattern of involvement. The following three patterns of lymphomatous involvement were defined: focal, diffuse, and mixed. Distribution of the lymphomatous infiltrate was noted to be paratrabecular, intertrabecular, or mixed (both paratrabecular and intertrabecular). Extent of involvement was categorized as less than 30% replacement of the bone marrow section by lymphoma, 30% to 70% replacement, and greater than 70% replacement. Prominent vascularity and fibrosis were noted, when present. The lymphoma cells in trephine biopsy or clot section were classified according to the predominant cell size into large-cell, mixed largeand small-cell, and small-cell. Patients with "pure" large-cell or mixed large- and small-cell were analyzed together for survival analyses. Actuarial survival probability curves were plotted according to the method of Kaplan and Meier.s3 Different curves were statistically compared using the log-rank test." RESULTS
As classified according to the Working Formulation, there were 54 cases (17%) of low-grade, 180 cases (57%) of intermediate-grade, and 76 cases (24%) of high-grade lymphoma (Table 2). There were 27 composite lymphomas that were classified according to the component with the highest grade (27 intermediate, one high). Seven lymphomas could not be further classified. Of 221 cases that were immunophenotyped, 196 (89%) were B-cell lymphomas and 25 (11%) were T-cell lymphomas. Benign lymphoid aggregates were detected in 28 bone marrow biopsies or clot sections, an incidence of 9% (Table 3). They appeared to be equally common in men and women (13 v 15). The median age of patients with benign lymphoid aggregates was 70 years (range, 46 to 83 years). Benign,lymphoid aggregates were slightly more common in patients with intermediate- and high-grade lymphoma than in those with lymphoma of low grade (9% v 6%). Benign lymphoid
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BONE MARROW INVOLVEMENT BY NHL Table 2. Lymphoma Classification by Lymph Node Histology and Incidence of Bone Marrow Involvement at Diagnosis Bone Marrow Involvement (%)
Lymph Node Histology
N (%)
Low-grade Small lymphocytic Follicular small-cleaved Follicular mixed Mantle zone
54(17) 18(5.7) 13(4.1) 22 (7.0) 1(0.3)
21(38.9)
180 (56.8) 27 (8.5) 15(4.7) 10(3.2) 24(7.6) 78 (24.7) 26(8.2)
64 (35.5)
76(24.0) 69(21.9) 1(0.3) 5 (1.6) 1(1.3)
14(18.4) 12(17.4) 1(100) 1 (20) 0 (0)
Intermediate-grade Follicular large-cell Diffuse intermediate Diffuse small-cleaved Diffuse mixed Diffuse large-cell Composite High-grade Immunoblastic Lymphoblastic Small-noncleaved Composite Not otherwise classifiable Total
7(2.2) 317
8(44.4) 4(30.8) 8 (36.4) 1(100)
9 (33.3) 11 (73.3) 4(40) 8 (33.3) 24 (30.8) 8 (30.8)
4(57) 102 (32.2)
NOTE. Includes positive trephine biopsy, clot section, and/or marrow aspirate smear.
aggregates were present in only one case of T-cell lymphoma. One hundred two patients (32%) had bone marrow involvement at diagnosis. Of these patients, 99% (101 of 102) had at least one trephine biopsy (23% had bilateral biopsies), 78% (80 of 102) had clot sections, and 82% (85 of 102) had bone marrow aspirate smears available for review. It is not known how many patients with negative bone marrows underwent these studies, but one would assume similar numbers. The trephine biopsy was positive in 96 patients (30%), the clot section alone was positive in an additional four patients, and only the aspirate smear was positive in two patients. The trephine biopsy was the only positive bone marrow specimen in 29 patients. One patient with follicular large-cell lymphoma had peripheral blood involvement, but lymphoma could not be definitively diagnosed in the bone marrow specimens available. In those patients with bone marrow involvement, the sensitivity for a positive trephine biopsy was 94% (96 of 102), for clot section 65% (52 of 80), and for aspirate smear 46% (39 of 85). Of the 96 patients with positive trephine biopsies, 48 (50%) also had positive clot sections, and 37 (38%) also had positive aspirate smears.
The frequency of bone marrow involvement at diagnosis varied with the grade of NHL in the node (Table 2). Bone marrow involvement by lymphoma was present in 39% of low-grade, 33% of intermediate-grade, and 18% of high-grade lymphomas. Thirty-one percent (61 of 196) of all B-cell lymphomas, 29% (48 of 163) of the intermediate- and high-grade B-cell lymphomas, and 32% (eight of 25) of T-cell lymphomas (all intermediate- and high-grade) had bone marrow involvement. Less than 30% of the bone marrow was replaced by lymphoma in 49 patients (51%), 30% to 70% in 19 (20%), and greater than 70% in 28 (29%) (Table 4). This distribution, with the majority of patients having less than 30% of their marrow replaced by lymphoma, remained fairly constant for all histologies. Involvement of the marrow in T-cell lymphoma tended to be more extensive than in B-cell lymphoma: 88% of the patients had greater than 30% involvement compared with 43% for B-cell lymphoma. The pattern of involvement was focal in 60 patients (63%), diffuse in 30 (32%), and mixed in five (5%). This distribution also remained fairly constant for all histologies. However, T-cell lymphomas had more diffuse or mixed involvement, and B-cell lymphomas had more focal involvement. The lymphomatous infiltrate was paratrabecular in location in 26 patients (28%) and intertrabecular in 25 (27%), and infiltrates were both paraand intertrabecular in 43 patients (46%), often in association with a packed marrow. This pattern remained constant for most histologies; however, the high-grade lymphomas tended to have more intertrabecular infiltrates. T- and B-cell lymphomas had a similar distribution. Increased vascuTable 3. Results in 28 Patients With Benign Lymphoid Aggregates Characteristic
Result
Male:female Age Range Median Overall incidence Incidence in low-grade NHL Incidence in intermediate- and highgrade NHL Incidence in unclassified NHL Incidence in B-cell NHL Incidence in T-cell NHL
13:15
%
46-83 years 70 years 28/317 3/54
8.8 5.5
24/256 1/7 24/196 1/25
9.4 14.3 12.2 4
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CONLAN ET AL Table 4. Extent and Pattern of Bone Marrow Involvement by Lymphoma at Diagnosis
Lymph Node Histology
Number With Bone Marrow Involvement*
Pattern of Bone Marrow Involvement (%)
Extent of Bone Marrow Involvement (%) < 30%
30%-70%
> 70%
Focal
19(19.8) 28(29)
60(63)
Diffuse
Mixed
Location of Bone Marrow Involvement (%) ParaIntertrabecular trabecular Mixed
Total
96
49(51)
30(31.5) 5(5.3)
26(27.6) 25(26.6) 43 (45.7)
Low-grade Intermediate-grade High-grade
21 57 14
12(57) 4 (19) 5 (24) 14(66.6) 6(28.6) 1(4.8) 27(47.4) 13(22.8) 18(31.6) 36(63.2) 17(29.8) 3(5.3) 7 (50) 4(28.6) 3(21.4) 8(57.1) 5(35.7) 1 (7.1)
7(33.3) 5(23.8) 9(42.9) 17(29.8) 13(22.8) 25(43.8) 1(7.1) 7 (50) 6 (42.9)
Small lymphocytic Small-cleaved, follicular, and diffuse Diffuse small irregular lymphocytic Mixed, follicular, and diffuse Large-cell, follicular and diffuse Immunoblastic Composite lymphoma
8
3(37.5)
1 (12.5)
4(50)
4(50)
4(50)
8
5(62.5)
1 (12.5)
2 (25)
5 (62.5)
9 14
4(44.4) 6(42.9)
4(44.4) 6(42.9)
1 (11.1) 2(14.2)
7(77.7) 9(64.3)
30 12 8
13(43.3) 7(58.3) 7(87.5)
5 (16.6) 2(16.6) 0(0)
12(40) 17(56.6) 12(40) 1 (3.3) 3(25) 7(58.3) 4(33.3) 1 (8.3) 1 (12.5) 7(87.5) 1 (12.5) 0(0)
B-cell
61
35(57.4)
10(16.4)
16(26.2) 45(73.8) 15(24.6) 1(1.6)
T-cell
8
1(12.5)
4(50)
3(37.5)
3(37.5)
0(0)
2 (25)
2 (25)
4 (50)
3 (37.5) 0(0)
3(37.5)
2 (25)
3 (37.5)
0(0) 1 (11.1) 3(21.4) 2(14.2)
3(33.3) 6(42.9)
1 (11.1) 4(28.6)
4(44.4) 4(28.6)
9 (30) 1 (8.3) 1(12.5)
6 (20) 14(46.6) 6 (50) 5 (41.7) 3(37.5) 4(50)
3(37.5) 2(25)
17(27.9) 15(24.6) 29(47.5) 3(37.5)
3(37.5)
2(25)
*Includes only those with positive trephine biopsy.
larity was detected in only six patients. Prominent fibrosis was present in three patients with diffuse large-cell lymphoma, diffuse mixed lymphoma, and composite lymphoma. Discordant histologic appearance between lymph node and bone marrow was observed in 41 patients (40% of those with positive bone marrows) (Table 5). In 41 of the 42 cases, it involved the presence of a high- or intermediate-grade lymphoma in the lymph node and a different intermediate (ie, less aggressive) or low-grade lymphoma in the bone marrow. The exception was a follicular mixed lymphoma in lymph node and large-cell lymphoma in bone marrow. In all other cases of low-grade lymphoma in the lymph node, the bone marrow also contained low-grade lymphoma. If only those patients with complete discordance between lymph node and bone marrow (ie, large-cell lymphoma at one site and small-cell lymphoma at the other site) are considered, the incidence of discordance is only 21% (21 of 102) and occurred only in the setting of large-cell or immunoblastic lymphoma in the lymph node. Of the lymphomas that were immunophenotyped and had bone marrow involvement, 52% of the B-cell lymphomas and 38% of the T-cell lymphomas showed discordant histology between lymph node and bone marrow; this represents 16% of all the B-cell lymphomas and
12% of all the T-cell lymphomas. When only the intermediate- and high-grade lymphomas were considered, discordant histology was present in 46% (22 of 48) of the B-cell lymphomas and 25% (two of eight) of the T-cell lymphomas (P = NS). Pattern, extent, and location of bone marrow involvement were similar for lymphomas with and without discordance when immunophenotype and only the pure nodal large-cell versus marrow small-cell histology were considered. For B-cell lymphomas with histologic discordance, marrow involvement tended to be minimal: 68% (13 of 19) had less than 30% marrow involvement (compared with 57% for all B-cell lymphomas with marrow involvement). The involvement was focal in 79% (compared with 74%) and paratrabecular in 53%. The T-cell lymphomas with discordant histology all had extensive marrow involvement (> 50%). When all histologic subtypes were included, patients with bone marrow involvement had a worse prognosis, as determined by actuarial survival, than those without marrow involvement (P = .02, Fig 1). However, patients with lowgrade lymphoma and bone marrow involvement fared no worse than those without marrow involvement. Patients with intermediate- and highgrade lymphomas and marrow involvement had a shorter survival than those without marrow
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1167
BONE MARROW INVOLVEMENT BY NHL Table 5. Comparison of Lymph Node and Bone Marrow Lymphoma Number with Positive Bone Marrow
Lymph Node Histology Large-cell and immunoblostic
43
Mixed Follicular
14 8
Bone Marrow Histology
No.
%
Large-cell Mixed Small-cell Composite
10 10 21 2
23 23 49 5
6
Diffuse
Small-cell (small lymphocytic, intermediate or small-cleaved)
26
Large-cell Mixed Small-cell Large-cell Mixed Small-cell
1 2 5 1 2 3
Small-Cell
26
12.5 25 62.5 17 33 50
100
NOTE. Includes only those with positive trephine biopsy. Excludes those with node histology of composite lymphoma (N = 8), lymphoblastic lymphoma (N = 1), small-noncleaved lymphoma (N = 1), and not otherwise classifiable (N = 4).
involvement (P = .03). When intermediate- or high-grade lymphomas were analyzed separately, bone marrow involvement did not significantly affect survival for the intermediate-grade lymphomas (P = .13) but high-grade lymphomas with marrow involvement had a much worse prognosis than those without marrow involvement (P = .007). Those patients with intermediate- and highgrade lymphomas with large-cell lymphoma in their bone marrow had a worse prognosis than those with small-cell lymphoma in their marrow (P = .05, Fig 2). Survival was significantly worse for patients with large-cell lymphoma in their marrow compared with those without marrow involvement (P = .03, Fig 2). However, survival was similar for patients with small-cell lymphoma in the marrow and those without marrow involvement. Similar results were found when
only intermediate-grade lymphomas were considered in the analysis. Survival was similar for all patients with B-cell or T-cell lymphomas. However, patients with stage IV B-cell NHL survived longer than those with stage IV T-cell NHL (P = .03), and when only patients with marrow involvement were compared, patients with T-cell lymphoma had significantly shorter survival (P = .02, Fig 3). This difference persisted when only those patients with intermediate- and high-grade NHL were included (P = .05). When B-cell lymphomas were analyzed independently, bone marrow involvement did not significantly affect survival, even when low-grade lymphomas were excluded. However, bone marrow involvement in T-cell lymphoma resulted in shorter survival com0)t
1-
C
0.8C
0.6-
.2_ .c
0.6-
Bone Marrow Negative
2 0.-
0
cl
Marrow Negative
0.4Small Cell in Marrow
0.2-
0
BoneMarrow -Posive Bone Marrow Positive
a0 0.2-0.
0S25
S
75
Survival in Months
Fig 1. Survival of all 317 patients based on the results of bone marrow examination. Patients without bone marrow involvement had a superior survival (P = .02).
L
Large Cell in Marrow
00
10
20
30
40
50
60
70
Survival in Months
Fig 2. Survival of patients with intermediate- and highgrade NHL based on presence and type of marrow involvement. Patients with large-cell NHL in the marrow have a worse prognosis than those with negative marrows (P = .02) and those with small-cell lymphoma in the marrow (P = .05).
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1168 0n
CONLAN ET AL
10.8-
C
rr CO
2 0
0.6-
BT-Cell NHL
0.4-
a
0.2-
2 a.
0-
T-Cell NHL ,
0
10
20
30 ,
,
40
50
60
,
70
Survival in Months Fig 3. Patients with B-cell NHL with marrow involvement survived longer than similar patients with T-cell NHL
(P = .02).
pared with those without marrow involvement (P = .05).
The presence of benign lymphoid aggregates in the bone marrow did not affect survival. This was true both for the low-grade lymphomas as well as for the intermediate- and high-grade lymphomas. Survival was similar for all patients regardless of extent of replacement of the bone marrow by lymphoma when all histologies were considered together. No significant differences in survival were observed when low-grade lymphomas were analyzed alone; however, the numbers were small. When intermediate- and high-grade lymphomas were analyzed as a group, survival was significantly different for those with greater than 70% marrow replacement compared with those with less than 30% marrow replacement by lymphoma (P = .03). No survival differences were observed between the group with 30% to 70% replacement and the other two groups. Pattern of involvement was also of prognostic significance for the intermediate- and high-grade lymphomas. Patients with focal involvement survived longer than those with diffuse involvement (P = .02). However, location of infiltrate (paratrabecular v intertrabecular) had no impact on survival. DISCUSSION
Using the Working Formulation, we found an overall incidence of bone marrow involvement with lymphoma at time of diagnosis of 32%. As emphasized by other investigators,2,3,5,8,10,11 we found the trephine biopsy produced a higher yield than either clot section or aspirate smear. The trephine biopsy failed to detect marrow involvement that was noted on clot section or aspirate smear in only six patients (2%).
We found a fairly uniform frequency of marrow involvement by NHL for both low and intermediate histologies (39% and 36%, respectively) and a low frequency of involvement in the high-grade lymphomas (18%). Some previous studies, using the Rappaport classification, have reported a higher incidence of marrow involvement in the low-grade lymphomas usually in the range of 50% to 60%,4,5,7,'1011.18 but others have reported an incidence closer to our own.2,8,9,16,19
In interpreting our data on low-grade lymphomas, it must be pointed out that our study only included those patients treated with combination chemotherapy; therefore, patients who may have been treated with radiation therapy, noncombination chemotherapy, or observation were excluded. Previous investigators have generally found a lower incidence of marrow involvement in the large-cell histology (histiocytic lymphoma of Rappaport), in the range of 10% to 20%,2,4,5,7,16,18,20'32,33
compared with our observed
frequency of 31% for diffuse and 33% for follicular large-cell lymphoma. If immunoblastic lymphoma is included with the intermediate lymphomas, as may have been the case in past studies, an incidence of bone marrow involvement of 25% is obtained, closer to that reported in the literature. There are no previous reports that comment on bone marrow involvement in the high-grade lymphomas other than for diffuse undifferentiated (small noncleaved) lymphoma, in which there has been a wide range of 0% to 67% reported.4 '8' 16' 18'19 Only one of our five patients with this diagnosis had marrow involvement. As has been previously reported,2 3 the diffuse small irregular lymphocytic (ie, diffuse intermediate) lymphomas had a very high incidence of marrow involvement (73%). The presence of marrow involvement by lymphoma was of no prognostic significance for patients with low-grade lymphomas. This was true when patients with stage IV disease with marrow involvement were compared with stage III patients or with stage IV patients without marrow involvement. This confirms the observation noted by Bennett et a134 and suggests that bone marrow biopsy may be of no value in the staging of patients with stage III low-grade lymphoma. As noted by others,32-34 we found that bone marrow involvement by lymphoma in the intermediate- and high-grade lymphomas carries
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BONE MARROW INVOLVEMENT BY NHL
a poor prognosis. In a univariate analysis, Fisher et a132 found bone marrow involvement to carry a worse prognosis than any other site of involvement. Armitage et a133 found that bone marrow involvement in diffuse histiocytic lymphoma carried a poor prognosis. However, in a multivariate analysis, Shipp et al" found that bone marrow involvement did not alter prognosis. The presence of bone marrow involvement in the intermediate- and high-grade lymphomas did not affect survival when compared with other stage IV patients without marrow involvement or to stage III patients. This finding does not support the report by Bennett et a134 that survival in stage IV patients with diffuse histiocytic and diffuse mixed lymphoma with marrow involvement is worse than in patients with stage III disease. However, we did include a more diverse group of patients than Bennett et al. They also noted similar survival for stage IV patients with or without marrow involvement. Considerable diversity has been noted in the degree and pattern of bone marrow involvement by lymphoma. Most patients with nodular poorly differentiated lymphocytic lymphoma have been reported to have focal infiltrates, frequently paratrabecular in location, and often replacing less than 30% of the bone marrow. 4 9 "-11Our patients with low-grade lymphoma also tended to have focal disease with less than 30% marrow involvement, but a paratrabecular location was not striking. Bone marrow involvement by intermediate- and high-grade lymphomas also tended to be focal with less than 30% marrow replacement and showed no predilection for a paratrabecular location. Others have reported significant diversity in bone marrow findings in large-cell lymphoma. 9 We found no difference in survival for patients with low-grade lymphoma for the various degrees and patterns of bone marrow infiltration. However, in the intermediate- and high-grade lymphomas, greater than 70% marrow replacement by lymphoma and a diffuse pattern of involvement were associated with a worse prognosis. Location of infiltrates did not correlate with survival. Foucar et al' 0o,1 have reported on the degree and pattern of marrow involvement in B- and T-cell lymphomas. They found B-cell lymphomas tended to be focal and paratrabecular in location with less than 30% marrow replacement,
whereas T-cell lymphomas tended to be nonparatrabecular or diffuse but also tended to replace less than 30% of the marrow. Hanson et a136 reported similar results but with a slightly higher degree of marrow replacement. They also noted a high incidence of polycellular reactive infiltrate, prominent vascularity, and necrosis. Our patients with T-cell lymphoma had both focal and diffuse marrow infiltration with an equal distribution between paratrabecular and nonparatrabecular location. We also noted that patients with T-cell lymphoma tended to have a higher degree of marrow infiltration than the B-cell group. The significance of discordant histologic subtypes of NHL between lymph node and other sites of involvement by lymphoma at diagnosis has been noted by Fisher et a137 and Mead et al. 25 When two subtypes with different prognoses are found at different sites, the prognosis may be intermediate. 37 Discordance has also been re11 14 21 25 ported for lymph node and bone marrow. ' , , Both large-cell lymphoma in lymph node with 11 14 24 small-cell lymphoma in bone marrow, , ,21, and small-cell lymphoma in lymph node with large-cell lymphoma in bone marrow 11' 14 have been reported. Jagannath et a12l in a study evaluating only patients with diffuse large-cell lymphoma found that 10 of 61 (16%) patients with large-cell lymphoma in lymph node biopsy also had large-cell lymphoma in their marrow, but 11 of 61 (18%) had small-cell lymphoma in their bone marrow. However, when only those patients with bone marrow lymphoma are considered in the analysis, 52% of patients had histologic discordance. Patients with large-cell lymphoma in their marrow had a worse prognosis (P = .01) than either patients with small-cell lymphoma in their marrow or a negative marrow. Bartl et a1' 4 also compared node histology to bone marrow histology and included all histologic subtypes. They found a 24% incidence of discordance, which included both lower grade and higher grade lymphoma in the marrow compared with lymph node. Fisher et al37 reported a 33% incidence of discordant histology when all histologies were considered and two or more positive biopsy sites were available for review. Eighteen percent were discordant in diffuse versus nodular pattern, and 15% were discordant in cellular type. Mead et a125 reported a much lower incidence of discordance: 9.3% overall, and 4.8%
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CONLAN ET AL
when comparing "favorable" to "unfavorable" histology. However, they do not report how many of these patients had at least two anatomic sites biopsied. Therefore, their figure may be falsely low. We found a 40% incidence of discordance between lymph node and bone marrow when considering only those patients with marrow lymphoma. However, this is reduced to 21% when only those patients with large-cell lymphoma in lymph node and small-cell lymphoma in bone marrow are included (ie, excluding "mixed" histology). Our inclusion of the mixed histology lymphomas as discordant if both sites were not mixed may therefore explain the high incidence of discordance that we observed, as may the differing ways in which discordance has been reported in the literature (Table 6). There was complete concordance for all but one lowgrade lymphoma. We found that patients with intermediate- and high-grade NHL and largecell lymphoma in the bone marrow had a worse prognosis than those with small-cell lymphoma in the bone marrow (P = .05), and that patients with small-cell lymphoma in the marrow do no worse than those with negative marrows. Although the discordant small-cell histology in the bone marrow was associated with minimal marrow involvement (< 30% in 68%, primarily focal), this was the pattern that was observed for the majority of bone marrow infiltrates. The small-cell histology was, however, more commonly associated with a paratrabecular location, suggesting a follicular center origin. For the aforementioned reasons and the lack of fulfillment of the criteria for benign lymphoid aggregates, we believe that these lymphoid infiltrates truly represented lymphomatous involvement of the marrow. In all cases but one, the discordance involved an intermediate- or high-grade lymphoma on lymph node biopsy and a low-grade or
intermediate-grade lymphoma in the bone marrow (Table 5). Two-hundred twenty-one patients with NHL in our study were immunophenotyped; 89% marked as B-cell lymphomas and 11% marked as T-cell lymphomas. All of the T-cell lymphomas were of intermediate- and high-grade. Bone marrow involvement was present in 31% of the B cell-lymphomas (29% of the intermediate- and high-grade) and 32% of the T-cell lymphomas. Foucar et a110'o11have reported a similar incidence of bone marrow involvement for B-cell lymphomas (51%) but a much higher incidence of marrow involvement for the T-cell lymphomas (65%). Hanson et al, 36 reporting from the same institution, found an 80% incidence of bone marrow involvement at diagnosis for T-cell lymphoma. However, Weisenburger et a138 reporting on 39 cases of T-cell lymphoma (some of which are included in this report), and Coiffier et al,39 reporting on 63 cases of T-cell lymphoma, found an incidence of marrow involvement of only 28% and 22%, respectively, more in agreement with our own findings. Similarly, Greer et al4° reported a 37% incidence of bone marrow involvement in T-cell lymphoma at diagnosis. Although a slightly higher incidence of discordant histology was observed for the intermediate- and high-grade lymphomas of B-cell immunophenotype than for the T-cell lymphomas, this was not statistically significant and does not explain the poorer prognosis associated with bone marrow involvement in the T-cell lymphomas. In conclusion, we have found that bone marrow biopsy in the low-grade lymphomas offers little information of prognostic significance but provides much useful information in the intermediate- and high-grade lymphomas. A high incidence of bone marrow involvement was found for the intermediate-grade lymphomas, and its pres-
Table 6. Incidence of Discordant Histology in the Literature Histologies Considered Diffuse large-cell All All All All Intermediate- and high-grade
Anatomic Sites Node v bone Node v bone > 2 Not reported Node v bone Node v bone
marrow marrow
marrow marrow
Discordance (%)
Reference
11/21 (52) 29/120 (24) 33/101 (33) 30/323 (9.3) 41/102 (40) 24/49 (49)
Jagannath et a121 Bartl et al4 Fisher et al" Mead et a125 Present series Present series
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BONE MARROW INVOLVEMENT BY NHL
ence correlated with decreased survival. In these patients, the distinction between large-cell and small-cell lymphoma in the marrow was important and proved to be prognostically significant. Bone marrow involvement in T-cell lymphomas
was associated with a poor prognosis, possibly due to the more extensive lymphomatous involvement seen with this immunophenotype. Thus, bone marrow biopsy remains a useful tool in the staging of patients with large-cell lymphoma.
APPENDIX Members of the Nebraska Lymphoma Study Group Who Participated in This Study University of Nebraska Medical Center
James O. Armitage, MD Philip J. Bierman, MD Douglas Harrington, MD James Linder, MD David Purtilo, MD Dennis D. Weisenburger, MD James A. Maillaird, MD P. Steven Johnson, MD David Gnarra, MD Herbert A. Hartman, MD Bernard Korbitz, MD Robert M. Langdon, MD David Silverberg, MD Gamini Soori, MD Vincent Bjorling, MD William M. Packard, MD John Casey, MD Monroe D. Dowling, MD Mark Hutchins, MD Timothy Judge, MD Daniel F. Moravec, MD W. Cary Peterson, MD Scot Sorensen, MD Warren Pevnik, MD David Howe, MD John Okerbloom, MD Robert Warner, MD Robert F. Thompson MD George K. Bascom, MD Thomas Buroker, DO Roscoe Morton, MD Robert Shreck, MD Mark Westberg, MD
Creighton University Omaha, NE
Scottsbluff, NE Lincoln, NE
North Platte, NE Hastings, NE Council Bluffs, IA Yankton, SD Kearney, NE Des Moines, IA
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