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Prognostic Value of Lymphocyte Homing Receptor and
S Phase Fraction in Non-Hodgkin’s Lymphoma
By Sirpa Jalkanen, Heikki Joensuu,
and Pekka Klemi
Lymphocyte homing receptors (HRs) mediate lymphocyte
binding to high endothelial venules, and control their
circulation between the blood and the lymphoid organs.
The role of HRs and nuclear DNA content in the spread and
prognosis of non-Hodgkin’s lymphoma was studied from
paraffin-embeddedtumor sections of 104 patients followedup for the minimum of 5 years after the diagnosis. HR
expression was analyzed by staining with a monoclonal
antibody, Hermes-3, and DNA content by flow cytometry.
Ten (10%) lymphomas were HR negative (HR-), 14 (13%)
weakly (HR+/-), and 80 (77%) strongly positive (HR+).
HR- lymphomas disseminated less often than HR / - or
HR+ lymphomas ( P = .03), and their prognosis was more
favorable ( P = .03), although they often had a large S
phase fraction (SPF), indicating a rapid proliferation rate. A
large SPF (greater than 12%) was strongly associated with
an unfavorable histologic type in Working Formulation
( P = .0001) and poor survival (P= .006), whereas DNA
aneuploidy was not. The 5-year survival rate corrected for
intercurrent deaths was 61% in lymphomas with SPF less
than 12% or with HR-, but only 15% if SPF was greater
than 12% and HR+ ( P < .OOOl). In multivariate analysis
stage ( P< .OOl),SPF ( P = .002) and HR ( P = .003) were
the only independent prognostic factors.
0 1990 by The American Society of Hematology.
U
gested that H R expression correlates with the extent of
lymph node in~olvement.’~
Picker et all4 found that Hermesdefined H R expression was higher in disseminated diffuse
large cell lymphoma than in nondisseminated disease, but the
difference did not achieve statistical significance, and no
follow-up was available. Pals et
on the other hand, found
a highly significant correlation between the H R expression
and dissemination of large cell lymphomas.
The nuclear DNA content of thousands of cells can be
determined in a few minutes by flow cytometry. By this
technique, an abnormal D N A content (DNA aneuploidy)
has been found in about 30% of non-Hodgkin’s lymphomas.16
Unlike in many epithelial cancers, D N A aneuploidy is
probably not a major determinant of survival in lymphomas;
but a large percentage of S phase cells, calculated by a simple
procedure from the D N A histogram, has correlated well with
poor prognosis.I7
In this study, tumors of 104 patients with nomHodgkin’s
lymphoma were analyzed for the expression of lymphocyte
HRs, using Hermes-3 MoAb, and for the nuclear D N A
content, and the data was correlated with histologic classification, clinical behavior of lymphoma, and the final outcome
of the patients. The results indicate that H R negative
( H R -) lymphomas seldom disseminate and have good
prognosis even if they have a large fraction of proliferative
cells, and that both H R and S phase fraction (SPF) are
+
NLIKE HODGKIN’S disease, the non-Hodgkin’s lymphomas form a heterogeneous group of diseases with
variable biologic behavior, ranging from well-differentiated
lymphocytic lymphomas, which may be followed-up without
treatment, to very aggressive forms of the disease, such as
lymphoblastic lymphoma or Burkitt’s lymphoma, which may
be fatal within a few months. The type of treatment is chosen
based on factors such as patient age and condition, presence
of B symptoms, stage, and histologic subtype of lymphoma.
However, these factors may fail to predict the biologic
behavior, aggressive chemotherapy with its hazards may be
given to patients not needing it, and follow-up without
treatment, single agent chemotherapy, or radiotherapy may
be selected for a patient in need of combination chemotherapy. None of the several histologic classifications available is
universally accepted, and all staging examinations may miss
small deposits of lymphoma.
Mature lymphocytes circulate continuously between the
blood and lymphoid organs in the body.’ In lymphatic tissues
and at sites of chronic inflammation, lymphocytes leave the
blood by selectively binding to specialized venules, so called
high endothelial venules (HEV).’ This binding is mediated
through homing receptor (HR) molecules that have been
identified in the mouse, rat, and h ~ m a n .Although
~.~
functionally mediating lymphocyte-endothelial cell interaction and
therefore named as homing receptors, recent cloning data
indicate that MEL- 144efined homing receptor in mouse
and Hermes-defined human receptor a r e structurally
In humans, 85 to 95 Kd glycoprotein class
(CD44), defined by a Hermes-series of monoclonal antibodies (MoAbs), mediate lymphocyte binding to peripheral
lymph node, mucosa-associated lymphatic tissues, and inflamed joint tissue (synovium).” Furthermore, expression of
this glycoprotein class correlates well with the HEV-binding
capacity of in vitro growing human lymphoma and lymphoblastoid cell lines.6
An animal study has indicated that lymphomas, which
bind well to HEV and thus possess functional HRs, disseminate hematogenously to all lymph node groups when injected
intramuscularly into syngenic recipients, whereas nonbinding lymphomas do not spread via the blood, and involve only
the nodes draining local tumor a t the site of injection.” A
small preliminary study with human lymphoma also sugBlood, Vol 75, No 7 (April l ) , 1990: pp 1549-1556
~
From the Departments of Medical Microbiology, Radiotherapy,
and Pathology. University of Turku and Turku University Central
Hospital, Finland.
Submitted February 27. 1989; accepted December 8,1989.
Supported by grants from the Finnish Cancer Foundation. the
Research and Science Foundation of Farmos. the Sigrid Juselius
Foundation, Turku University Foundation, and the Finnish Academy.
Address reprint requests to Sirpa Jalkanen, MD, PhD, Department of Medical Microbiology, Turku University,SF-20520 Turku,
Finland.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1990 by The American Society of Hematology.
0006-4971/90/7507-0016$3.00/0
1549
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1550
JALKANEN, JOENSUU, AND KLEMI
important a n d independent prognostic factors in nonHodgkin’s lymphoma, together with stage of t h e disease.
MATERIALS AND METHODS
Patients. One hundred four consecutive adult cases (age over 16
years) with histologically diagnosed non-Hodgkin’s lymphoma,
treated in Turku University Central Hospital (Finland) from 1970 to
1980, with adequate staging examinations done and sufficient
paraffin-embedded tumor material available were analyzed. Fiftysix (54%) of the patients were men and 48 women, the mean age at
the diagnosis was 59 years (range, from 20 to 86 years). Twenty-two
(21%) patients had B symptoms. All patients were followed-up for
the minimum of 5 years (range, from 5 to 17 years) or until death.
Histology. staging, and treatment. Formalin-fixed and paraffinembedded tissue blocks were sectioned and stained with the Giemsa,
hematoxylin and eosin, periodic acid-Schiff, methyl green and
pyronin, and van Gieson methods. The original diagnoses were
reviewed. Subclassification of the tumors was done according to the
Working Formulation.’* Hematopoietic origin of lymphomas was
confirmed with an MoAb against human common leukocyte antigen
(DAKO, Glostrup, Denmark). MoAb against chicken T cells (3G6)
used as serum-free culture supernatant served as a negative control
antibody. The bound primary antibodies were visualized using the
avidin-biotin complex technique (Vector Laboratories, Burlingame,
CA) with I,l-diaminobenzidine as the chromogen.
Staging of the lymphomas was done according to the Ann Arbor
classification system.” The clinical status, chest x-ray, bipedal
lymphography, bone marrow aspiration biopsy, and liver and spleen
scans were usually done as staging examinations. Laparotomy was
done only in cases with primary abdominal lymphoma. Thirty-one of
the patients had stage I, 30 stage 11, 21 stage 111, and 22 stage IV
disease at presentation. Because HRs are involved in lymphocyte
binding to HEV at sites where lymphocytes exit the blood, the
physiologic recirculation routes were taken into account when
analyzing dissemination. Hematogenous spread of lymphoma was
considered to be present if the dissemination pattern of lymphoma
either at diagnosis, recurrence, or autopsy could not be explained by
simple lymphatic drainage. For example, the presence of lymphoma
in the Waldeyer’s ring and in the cervical lymph nodes can be
explained with lymphatic spread, whereas bilateral cervical node
affision without detectable lymphoma in Waldeyer’s ring or elsewhere in the head was considered as hematogenous spread.
Stage I and I1 patients were usually treated with radiotherapy
(RT) or with the combination of radio- and chemotherapy, and stage
111 and IV patients were usually treated with chemotherapy only.
Involved fields, the mantle, and the “inverted Y” fields were used,
and the tumor dose was usually in the range from 4,000 to 4,500
cGy. The most commonly used chemotherapy combinations were
COP (cyclophosphamide, vincristine, and prednisone) and CHOP
(cyclophosphamide, doxorubicin, vincristine, and prednisone).
Flow cytometry. A representative paraffin embedded tissue
block was chosen for flow cytometry. A 5-pm control section was cut
immediately adjacent to the 50-pm section used for DNA content
analysis for light microscopy to ascertain that tumor tissue was being
analyzed. Paraffin was removed with xylene, and after rehydration in
a series of decreasing concentrations of ethanol, a single cell
suspension was prepared with 0.5% pepsin as described earlier.”
DNA was stained with propidium iodide.2’The resulting suspension
was filtered through a silk mesh before flow cytometry.
Flow cytometry was done with a FACStar flow cytometer (BectonDickinson Immunocytometry Systems, Mountain View, CA). A
488-nm argon ion laser line run at 600 mW was used for fluorescence
excitation. For each histogram, 20 x 10’ particles were measured.
Histograms of good quality were obtained; the coefficient of variation (CV) of diploid peaks usually ranged from 3% to 6%. All
samples were analyzed at least twice as described earlier.22
If only one G I peak could be seen in the DNA histogram,
lymphoma was considered to be diploid. Histograms with a skewed
G1 peak or a G1 peak with a “shoulder” in repeated analyses were
classified as near diploid. If two G1 peaks could be identified, the
tumor was considered to be aneuploid. Examples of histograms are
shown in Fig I . The DNA index was calculated from the ratio of the
modal channel numbers of the aneuploid and diploid peaks. Tetraploid lymphomas had a G1 peak in the tetraploid region (4N, DNA
index 1.9 to 2.1) and a corresponding G2/M peak in the octaploid
region (8N). The peak with the least DNA content was considered to
represent diploid cells. The percentage of S phase cells was calculated according to the rectangular method.” No computer correction
for possible cell debris was done. SPF was not calculated in six cases
due to an overlapping aneuploid population, and in two cases due to
excessive cell debris.
Staining of HRs. HR expression was determined using a monoclonal mouse antibody to human lymphocyte HR, Hermes-3, as
serum-free culture supernatant. Hermes-3 has been shown to recognize a common determinant of CD44 class of HRs mediating
lymphocyte binding to peripheral lymph node, mucosal, and synovial
HEV.” The production and specificity of this antibody have been
described earlier.” Hermes-3 was found to be the only antibody in
the Hermes series that worked on paraffin-embedded tissue sections,
but the staining patterns of Hermes-3 were comparable when tested
on normal tonsils and over 20 different lymphoma specimens both on
frozen and paraffin-embedded tissues (Fig 2). Hermes-3 staining
was scored - , + / - , and + ( - , negative; + / - ,weakly positive, a
definitive population of tumor cells positive; +, clearly positive, the
majority or all tumor cells positive). In all cases, variable number of
normal tumor infiltrating lymphocytes were seen, easily recognizable
with MTl antibody in B-cell lymphomas (positive with MB2
antibody; MT1 and MB2 antibodies were from Clonab, Viereich,
Germany). They all stained intensely with Hermes-3 and served as a
2000
E]
ANEUPLOID
TETRAPLOID
1300
01-1.13
0
I00
FLZ
200
0
01-2.00
100
200
FL2
Fig 1. Examples of DNA histograms produced from paraffinembedded tissue. The number of particles analyzed is given on the
vertical and DNA fluorescence ( F U ) on the horizontal axis. (A)
Diploid histogram with a low SPF (S,2.7%). (B) Diploid histogram
with a large SPF (15.2%). (C) Hyperdiploid lymphoma, SPF wrresponding to the diploid (d) and aneuploid (a) peaks is 8.7%. (D)
Tetraploid lymphoma, SPF of the tetraploid stemline of cells is
7.0%.
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LYMPHOCME HOMING RECEPTORS IN LYMPHOMA
1551
Fig 2. Hermesd antibody
gives comparable staining patterns on frozen and formalin
fixedlparaffin embedded sections. Frozen (A, C, and E) and
formalin fixed/pareffn embedded (6, D, and F) sections of
three different types of 6-41
lymphomas stained with Hermes3 antibody using immunoperoxidose method and hematoxylin
counterstain. (A and 6) Hermes3 - Burkitt's lymphoma. Practiwlty all cells in these fields are
tumor cells. (C and D) Large cell,
immunoblastic lymphoma, in
which both tumor cells and tumor infiltrating normal T lymphocytes are Hermes-3 + (E and F)
Hermes-3 + diffuse small lymphocytic lymphoma: both normal f
cells and tumor cells are Hermec
3r.
.
useful internal staining standard. Immunocytochemical staining of
twodifferent kinds of follicular lymphomas are presented in Fig 3.
Coding. The patients were provided with a numerical code to
prevent clinical data or survival information to interfere with
histologic. DNA histogram. or HR expression classifications. The
classifications were also done without knowledge of the results of the
other analyses.
Stutisticd unulyses. Survival analysis was done using a BMDP
computer program (BMDP Statistical Software, Department of
Biomathematics, University of California Press, Los Angeles).
Survival was estimated with the product-limit method, and comparison of survival between groups was done using the generalized
Wilcoxon test (BMDP IL). Both crude survival rate and survival
rate corrected for known intercurrent deaths were calculated. The
relative importance of prognostic factors was analyzed using Cox's
proportional hazard model (BMDP 2L). Frequency tables were
analyzed using the chi-square test and Fisher's exact test. The SPF
distributions of different groups were compared using KruskalWallis's analysis of variance and Mann-Whitney's U-test. All P
values are two-tailed.
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JALKANEN, JOENSUU, AND KLEMI
1552
Fig 3. A Hermes-3 - (A) and a Hermes-3+ (8) follicular lymphoma. ( C )Anti-MT1 staining of lymphoma in panel 8 showing T cells, and
(D) anti-MB2 staining showing 8-cell areas. Positive cells inside the germinal centers in (A) represent nonneoplastic T cells or
histiocyticldendritic cells.
follow-up (P= .03).Nine (64%) of the 14 patients with
H R + / - and 57 (71%) of the 80 patients with H R + disease
had evidence of hematogenous spread during the follow-up.
Six H R - lymphomas were Ann Arbor stage I at the time of
the diagnosis (P = .06). The patients with H R - lymphoma
are described in detail in Table I .
RESULTS
Homing receptor expression and DNA content. Ten
(10%) lymphomas were HR negative (-), and 14 (13%)
were weakly (+/-), and 80 (77%) clearly positive (+) for
HR. Three of the IO H R - and 66 of the 94 HR +/- or
HR + lymphomas disseminated hematogenously during the
Table 1. Characteristics of Patients W i t h HR - Lymphoma
Cwe
1
2
3
4
5
6
SsxlAgs
Hiadogv
M/55
F/75
M/53
M/6 1
F/33
M/74
Lymphoblastic B cell
Small cleaved cell, diffuse, B cell
Lymphoblastic B cell
Large cell, diffuse, 8 cell
Large cell. diffuse, B cell
Small cleaved cell, diffuse, unidentified
Small cleaved cell, follicular. B cell
Small lymphocytic B cell
Mixed. small cleaved and large cell,
follicular, B cell
Small cleaved cell, folliculer, 8 cell
7
8
9
F/70
F/30$
F/63
10
F/60
SPF(%)
Stage
Hematogemnn
Spread
38.4.
22.5
21.9
21.1
17.7
8.1
38
1AE
2AE
2BE
1A
1AE
Yes
No
No
No
No
Yeslt
COP, RT
RT
RT
Surgery
RT
RT
Dead, 23
Dead, 105 (cardiac death)
Alive, 65
Alive, 133
Alive, 125
Dead, 40
2.8
2.6
2.5
18
4A
1A
No
YeS
No
RT
Cyclophosphamide
RT
Alive, 87
Alive, 2 13
Alive, 106
2.1
1A
No
Surgery
Alive, 83
Treatment
Follow-up. Months
.Highest SPF measuredin the series.
tDisseminationuncertain. Stage I parotid lymphoma. the suspected recwent tumor in the abdomen was never histologically examined.
$Biopsies from the recunent tumors were positive for HR.
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1553
LYMPHOCME HOMING RECEPTORS IN LYMPHOMA
70r
DNA INDEX
Fig 4. Lymphomas grouped by t h e DNA index. The neardiploid lymphomas are given t h e value 1.05.
Sixty-four (61.5%)of the lymphomas were diploid and 12
(1 1 .5%) near-diploid. Twenty-eight (27%)lymphomas were
clearly aneuploid (includes five tetraploid tumors). The
DNA indices ranged from 1.00 to 2.07, and the most
aneuploid peaks were in the hyperdiploid region (Fig 4). SPF
ranged from 1.4%to 38.4%,mean 8.8%, S D 7.0%. HR- and
H R + / - lymphomas had higher SPFs than H R + lymphomas (P= .02). Four of the 10 H R - lymphomas had SPF
greater than 20% as compared with only 4 of the 86 H R
+/- or H R + lymphomas (P= .004).
SPF correlated well with Working Formulation. In low-,
intermediate-, and high-grade malignant lymphomas the
mean SPFs were 4.3% (SD, 2.8%), 8.4% (SD, 5.4%) and
14.6%(SD, 8.5%), respectively (Table 2). Only 1 (3%)of the
35 low-grade malignant and 7 (21%)of the 34 intermediate
malignant lymphomas had a large SPF (> 12%,see below),
whereas 15 (56%) of the 27 high-grade malignant lymphomas had SPF greater than 12%(P< .0001). H R expression
or D N A ploidy did not correlate significantly with the
histologic classification used.
HR expression and DNA content analysis in predicting
survival. D N A aneuploidy was not associated with survival
if the near-diploid cases were grouped together with the
aneuploid lymphomas (P = .84), or if they were classified
together with the diploid lymphomas. None of the D N A
index values were useful in prediction of the final outcome.
However, SPF was strongly associated with both crude and
corrected survival rate. After a series of calculations, the SPF
value 12%was found to be associated with most predictive
power. Only 26% of the patients with lymphoma with SPF
greater than 12% were alive 5 years after the diagnosis,
whereas 51% of the patients with a lymphoma with less than
12%S phase cells were alive (P = .006, Fig SA).
H R expression was also a significant factor determining
the overall survival. Eighty percent of patients with H R lymphoma survived for 5 years as compared with 44% of
H R + / - and H R + lymphomas (P= .03, Fig 5B).
Prognosis of H R - lymphomas was good even if the
lymphoma had a large SPF, suggesting a rapid proliferation
rate (Fig 6). Eleven of the 12 patients with an H R + or a
H R + / - lymphoma with greater than 15% S phase cells
Table 2. DNA Ploidy, Lymphocyte HR Expression, and S Phase Fraction of 104 Lymphomas Correlated With Working Formulation
Homing Receptor
Ploidy
Workina Formulation
Low-grade
Small lymphocytic, consistent with
CLL
Follicular, predominantly small
cleaved cell
Follicular, mixed small and large
cell
+
SPF: Mean %, ED%),
N
DI
ND
AN
-
+/-
22
17
2
3
1
2
19
13
7
2
4
2
2
9
4.7, (3.6), 1.4-13.2
2
1
1
0
1
0
1
2.5
2
17
8
12
0
10
6
6
1
2
1
1
1
5
1
5
0
0
2
0
2
2
1
2
13
6
9
10
13
1
4
6
9
0
2
2
0
0
0
2
4
1
2
0
2
0
0
3
2
0
0
7
9
1
4
104
64
12
28
10
14
80
Ranae %
4.2, (2.2) 2.0-9.5
Intermediate-grade
Follicular, predominantly large cell
Diffuse, small cleaved cell
Diffuse, mixed small and large cell
Diffuse, large cell
High-grade
Large cell, immunoblastic
Lymphoblastic
Small noncleaved cell
Miscellaneous
Total
Abbreviations: DI, diploid; ND, near-diploid; AN, aneuploid (includes tetraploid tumors).
2
5.0
8.5, (5.01, 2.4-22.5
8.2, (5.01, 3.1- 15.6
8.7, (6.5). 2.5-2 1.1
15.5, (4.9). 8.9-25.3
12.6, (10.4). 2.6-38.4
13.0
19.6, (8.6). 8.8-27.2
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JALKANEN. JOENSUU, AND KLEMI
1554
100
80
5Q
c
c
60
.
I
5
40
IA
Q
20
0
A
SPFS12%
+ SPF>lP%
10
20
30
40
50
60
time in months
loo
80
5Q
60
c
.
I
for detailed phenotyping of lymphomas, because many antibodies working on frozen tissues do not stain paraffinembedded samples. This is the case also with Hermes series
of MoAbs. Only Hermes-3 antibody, which identifies different epitopes of H R molecule(s) than Hermes-1 and -2,
stains HRs in paraffin-embedded tissue. Another difficulty in
retrospective series is that the known final outcome may
influence sample classification. This was solved by sample
coding.
Only 10% of lymphomas stained negatively for HR. This
may reflect the fact that most normal counterparts of
malignant lymphocytes have HRs, and only nonmigratory
lymphocytes, eg, most germinal center cells and cortical
thymocytes, lack HRs. However, the H R - lymphomas form
an important subgroup because they usually remain local,
even if they have an unfavorable histologic type and a large
S P F (Table 1, Fig 6 ) . Therefore, many of these lymphomas
may be curable with local therapy, such as radiotherapy
(Table l ) , and aggressive chemotherapy often recommended
for high-grade malignant lymphomas can be avoided.
At least 2, possibly 3, of the 10 HR- lymphomas gave rise
to hematogenous metastases (Table 1). Tumor heterogeneity
may partially explain this, since in one such case staining for
H R was repeatedly negative from the primary sample, but
repeatedly positive from a sample taken from a recurrent
b40
m
1
+ HR+or HR+/-
B
0
10
20
30
40
50
60
40
-
35
-
time in months
Fig 5. (A) Crude survival of 23 patients with a lymphoma with
SPF greater than 12%. and 73 with SPF c 12%. (61Crude survival
of 10 patients with HR--. and 94 with HR+ or HR+ / - lymphoma.
died within 3 years from the diagnosis, whereas only 1 of 5
such patients with a H R - lymphoma died (P = .01). The
corrected 5-year survival rate of the patients with H R + or
HR + / - lymphoma with S P F greater than 12% was only
13%, whereas 61% of the patients with lymphoma with either
negative H R or S P F less than 12% survived for 5 years
(P = .0001, Fig 7).
Presence of B symptoms (P = .16) did not correlate with
survival, but advanced stage (P< .0001), extralymphatic
site (P = .02), age greater than 40 years at diagnosis
(P = .03), and male sex (P = .04) were associated with
unfavorable outcome in univariate analyses. In multivariate
analysis, the only independent prognostic factors were stage
(P< .001), S P F (<12% v>12%, P = .002), and H R (HRv H R + / - a n d H R + , P = .003).
DISCUSSION
H R and S P F were found to be valuable prognostic factors
predicting survival in non-Hodgkin's lymphoma. Paraffinembedded tissue was used for analysis, because then long
follow-up was available. However, this puts some limitations
30 0
-s
:
25-
0
:
20U
I
a
8
15
0
0
?
0
5
0
HR N =IO
HR + IN=12
HR +
N =74
Fig 6. S phase fraction and homing receptor expression
correlated with the final outcome in 96 patients with nonHodgkin's lymphoma. (0).Alive after 5 years from the diagnosis;
(01,died from lymphoma: (W), died from an intercurrent cause.
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1555
LYMPHOCYTE HOMING RECEPTORS IN LYMPHOMA
100
80
2
60
OI
.->
2*
40
v1
2o
i
1
+Q
L
HR+
HR- oor +/r and
S SPF>12%
P F 5
0 : .
I
10
A 0
-
I
20
-
I
3
-
30
I
40
-
4
.
1
.
4
50
60
50
60
time in months
100
80
E 60
*
Q
.
I
e2 40
Q
HR- or SPFs12
c HR + or +/- and SPF>12
B
0
10
20
30
40
time in months
Fig 7. Crude (A) and corrected (B)survival for intercurrent
causes of 78 patients with a lymphoma with HR- or SPF 5 12%.
and 18 with HR or HR+ / - and SPF greater than 12%.
+
tumor. Lymphomas classified as + / - for H R behaved more
like H R + lymphomas than H R - lymphomas, suggesting
that if even a small proportion of lymphoma cells possess a
functional HR, lymphoma can disseminate hematogenously.
About 30% of H R + lymphomas remained local during the
follow-up. Hermes-defined CD44 class of H R molecules
alone may not be sufficient for lymphoma dissemination, but
other molecules, such as, for example, the human equivalent
of mouse lymphocyte homing receptor (MEL-14), the VLA4 molecule involved in lymphocyte binding to mucosal HEV,
and CD1 la/CD18 complex (LFA-I), may be needed.24s25
The CDI la/CDI 8 complex has been shown to be involved
also in normal lymphocyte binding to high endothelial
venules in a nonorgan-specific m a n r ~ e r . ~Further,
~ , ~ ’ immunohistologic detection of a molecule does not assure its normal
function; the HRs in these lymphomas may be nonfunctional.
On the other hand, also early treatment or host defense
mechanisms might have inhibited lymphoma dissemination
in these cases.
However, a major reason for some of the H R + lymphomas not giving rise to hematogenous metastases is probably
the relatively short follow-up. All patients with H R + lymphoma with a high SPF died within a few years (Fig 6 ) .
Despite its protracted clinical course, low-grade lymphoma is
often an eventually incurable disease, and many of the H R +
lymphomas with low SPF are likely to recur later. It will be
of interest to see if H R - low SPF lymphomas form a
genuinely curable subgroup of low-grade lymphoma.
In conclusion, the present study indicates that meaningful
lymphocyte H R and SPF analyses can be done from paraffinembedded archival material, even the fresh tissue would be
ideal. H R - non-Hodgkin’s lymphomas only seldom disseminate hematogenously, although they are often highly malignant and have a large fraction of proliferative cells. They also
may be curable by local treatment. Both lymphocyte CD44
class of H R and SPF determinations are important and
independent prognostic factors in non-Hodgkin’s lymphoma.
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B 159:257, 1964
2. Butcher EC: The regulation of lymphocyte traffic. Curr Topics
Microbiol Immunol 12835, 1986
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1990 75: 1549-1556
Prognostic value of lymphocyte homing receptor and S phase fraction
in non-Hodgkin's lymphoma
S Jalkanen, H Joensuu and P Klemi
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