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Steroid Receptors in Hereditary Breast
Carcinomas Associated with BRCA1 or BRCA2
Mutations or Unknown Susceptibility Genes
atural history is a major issue in the medical management of
women prone to hereditary cancer. Greater knowledge in this
area should help to define the most appropriate preventive strategies
for individuals with a high genetic risk1 and to guide the treatment of
affected family members with breast and/or ovarian carcinoma. In
clinical practice, morphologic parameters are of primary interest in
the initial classification of disease and in determining prognosis, as
well as in predicting the course of the tumor. Consequently, a particular pathologic presentation may call for subsequent specific investigations and treatments. There are now several lines of evidence for
major differences in morphoclinical presentation between sporadic
and hereditary cases that are thought to be associated with different
natural histories.2– 6
In this regard, the work of Loman et al.,7 who discuss the importance of steroid receptor status in hereditary breast carcinoma, is of
great interest. They found that estrogen receptor negativity is a prominent feature of BRCA1-associated breast carcinomas, whereas progesterone receptor negativity appears to be less discriminant. Because
steroid receptors are pivotal regulators of normal mammary cell
growth and differentiation, and because estrogen receptor negativity
is associated with a poor outcome for patients in population-based
studies, the authors believe that BRCA1-associated breast carcinomas
are hormone-independent tumors associated with a bad prognosis.
Convergent studies have shown that BRCA1-associated breast
carcinomas are predominantly early onset, high grade, highly proliferative, and poorly differentiated.2– 4,8 These features are known to be
correlated with steroid receptor status. Thus, the correlation of steroid
receptor status independently of other parameters deserves to be
tested in BRCA1-associated breast carcinomas. With this aim, we
compared 32 BRCA1-associated breast carcinomas from 22 families
with a BRCA1-germline mutation selected from the records of the
French Cooperative Network, and 200 consecutive controls from our
hospital-based registry. Common clinical and morphologic features,
including steroid receptor status and parameters such as age at onset,
grading, circumscription, mononuclear infiltrate, and p53 or ERBB2
expression, were analyzed by using the logistic regression model
(SPSS statistical software package, Version 6.1).
In multivariate analysis, only 3 parameters were significantly
different between the 2 populations: early age at cancer onset (P ,
0.0001; odds ratio [OR] 5 1.16 for each year), estrogen receptor
negativity (P 5 0.01; OR 5 5.7), and poor tubular differentiation (P 5
0.03; OR 5 5).
Our results reinforce those of Loman et al.7 with regard to the
pivotal place of estrogen receptor negativity in the phenotype related
© 1999 American Cancer Society
CANCER May 15, 1999 / Volume 85 / Number 10
Distribution of Typical Medullary and Nonmedullary Breast
Carcinomas in Controls and BRCA1-Associated Breast Carcinomas
According to Estrogen Receptor Status
Estrogen receptor (ER) statusa
Breast carcinoma
control cases
n 5 200
breast carcinomas
n 5 28
ER2 (%)
ER2 (%)
Typical medullary
breast carcinomas
6 (24)
breast carcinomas
70 (100)
19 (76)
70 (100)
25 (100)
Evaluation of ER status was done for 200 controls and 28 of 32 BRCA1-associated breast carcinomas.
The four BRCA1-associated cancers not tested were all nonmedullary. Immunohistochemical detection
of ER was done using ER1D5 monoclonal antibody (Immunotech, Marseille, France).
to BRCA1 germline mutations (in our series, 89% of
BRCA1-associated breast carcinomas were estrogen
receptor negative vs. 35% of controls). We also confirm
the lesser importance of progesterone receptor negativity in this category of tumor (in our series, 82% of
BRCA1-associated breast carcinomas were progesterone receptor negative vs. 50% in controls). Although it
was a significant factor in univariate analysis (P 5
0.0004), the significance of progesterone receptor negativity was not retained in multivariate analysis.
However, a striking and novel result was the finding that, although they are thought to characterize the
same phenomenon (i.e., the differentiation of the tumor), estrogen receptor status and tubular differentiation had almost equivalent odd ratios in our model,
implying that a certain degree of independence exists
between these two parameters in the BRCA1-associated breast carcinoma population.
Based on these results, two major issues must be
addressed. First, estrogen receptor negativity may not
always be associated with a poor outlook. For instance, typical medullary breast carcinoma, an excess
of which is observed among BRCA1-associated breast
carcinomas,9 is a subgroup of high grade tumors that
are frequently estrogen receptor negative and are associated with a particularly favorable course.10 In our
series of BRCA1-associated breast carcinomas, all the
typical medullary breast carcinomas were estrogen
receptor negative. This type of breast carcinoma represented almost 25% (P 5 0.0002, Fisher exact test) of
the estrogen receptor negative tumors in our BRCA1associated population (Table 1). Consequently, the
significance of steroid receptor status in terms of prog-
nosis should be analyzed with respect to the type of
the tumor as well as the genetic background. Thus,
estrogen receptor negativity could be regarded as a
feature of a phenotype that is under the control of a
specific pattern of carcinogenesis triggered by the
BRCA1 germline mutation, much more than the results of tumor progression.
Second, it is important to define the place of hormonal interventions and, more specifically, the use of
tamoxifen in the treatment of BRCA1 gene carriers. Estrogen receptor negativity is considered a marker of hormone insensitivity in the general population.11 Because
BRCA1-associated breast carcinomas are predominantly
estrogen receptor negative, under the assumption of a
similar effect than in the general population, adjuvent
tamoxifen therapy for this population is not worthwhile.
The discrepancy between early results from U.S. and
European trials12 regarding the efficiency of tamoxifen in
preventing breast carcinoma may be explained by the
finding that eligibility in the latter was based predominantly on strong family history. Because BRCA1 germline mutations account for a good proportion of hereditary cancer cases,8 protection by tamoxifen may be
reduced in this case. In France, experts have adopted a
cautious position1 regarding the use of antiestrogen
agents in the preventive medical management of
women prone to hereditary cancer.
Eisinger F, Alby N, Bremond A, Dauplat J, Espie M, Janiaud
P, et al. Recommendations for medical management of hereditary breast ovarian cancer: the French national Ad Hoc
committee. Ann Oncol. In press.
Eisinger F, Stoppa-Lyonnet D, Longy M, Kerangueven F,
Noguchi T, Bailly C, et al. Germ line mutation at BRCA1
affects the histoprognostic grade in hereditary breast cancer. Cancer Res 1996;56:471–74.
Marcus J, Watson P, Page D, Narod SA, Lenoir GM, Tonin
P, et al. Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 1996;77:
Johannsson O, Idvall I, Anderson C, Borg A, Barkardottir RB,
Egilsson V, et al. Tumor biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer 1997;33:362–
Verhoog L, Brekelmans C, Seynaeve C, van den Bosch LM,
Dahmen G, van Geel AN, et al. Survival and tumor characteristics of breast cancer patients with germline mutations
of BRCA1. Lancet 1998;351:316 –21.
Eisinger F, Noguès C, Birnbaum D, Jacquemier J, Sobol H.
Low frequency of lymph node metastasis in BRCA1-associated breast cancer. Lancet 1998;351:1633– 4.
Loman N, Johannsson O, Bendahl P-O, Borg A, Ferno M,
Olsson H. Steroid receptors in hereditary breast carcinomas
associated with BRCA1 or BRCA2 mutations or unknown
susceptibility genes. Cancer 1998;83:310 –9.
Ford D, Easton D, Stratton M, Narod S, Goldgar D, Devilee
P, et al. Genetic heterogeneity and penetrance analysis of
the BRCA1 and BRCA2 genes in breast cancer families. Am J
Hum Genet 1998;62:679 – 89.
9. Eisinger F, Jacquemier J, Charpin C, Stoppa-Lyonnet D,
Bressac-de Paillerets B, Peyrat JP, et al. Mutations at BRCA1:
the medullary breast carcinoma revisited. Cancer Res 1998;
58:1588 –92.
10. Reiner A, Reiner G, Spona J, Schemper M, Holzner J. Histopathologic characterization of human breast cancer in
correlation with estrogen receptor status. Cancer 1988;61:
1149 –54.
11. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised
trials. Lancet 1998;351:1451– 67.
12. Pritchard K. Is tamoxifen effective in prevention of breast
cancer? Lancet 1998;352:80 –1.
François Eisinger, M.D.
Department of Cancer Control and INSERM CRI 9703
Paoli-Calmettes Institute
Marseille, France
Jocelyne Jacquemier, M.D.
Department of Pathology and INSERM CRI 9703
Paoli-Calmettes Institute
Marseille, France
Catherine Noguès, M.D.
Genetic Oncology Unit
René Huguenin Center
Saint-Cloud, France
Daniel Birnbaum, M.D., Ph.D.
Laboratory of Tumor Biology and INSERM U 119
Paoli-Calmettes Institute
Marseille, France
Hagay Sobol, M.D., Ph.D.
Department of Genetic Oncology, INSERM CRI 9703,
and Laboratory of Tumor Biology
Paoli-Calmettes Institute
Marseille, France
Author Reply
here is growing evidence that BRCA1-related
breast carcinoma has typical morphologic features. BRCA1-related tumors are typically of ductal
type, with a high mitotic count, heavy lymphocytic
infiltration, and low steroid hormone receptor levels.
They are frequently c-erb B-2 negative, and a great
portion of the tumors have pushing margins. Compared with non-BRCA1-related tumors, they show
higher S-phase fractions and are more often nondiploid.1– 4 It has been suggested that their lymphocytic
infiltration is related to what is seen in typical medullary carcinoma, a tumor type associated with a favor-
able prognosis in spite of high grade features.5 Eisinger et al. have previously presented data indicating
that a large proportion of the breast tumors seen in
association with germline mutations in BRCA1 are of
the typical medullary type.6 However, in material from
southern Sweden, which includes most of the cases
presented in the article cited by Eisinger et al. in this
issue, we conclude that heavy lymphocyte infiltration
is a common feature of BRCA1-related tumors (Grade
3 lymphocyte infiltration occurs in 56%) but that these
tumors do not fulfill all the criteria necessary to be
classified as typical or atypical medullary carcinomas.1
In a recent article by Lakhani et al., the significance of
typical and atypical medullary cancers among the
BRCA1-related tumors displaying lymphocytic infiltration is also questioned.4
Early data suggested a relatively good prognosis
for patients with BRCA1-related breast carcinoma in
spite of negative prognostic factors.7,8 Evidence presented in these early studies is weak, and both studies
are based on analyses of cases without verified BRCA1
mutations. More recent findings indicate that BRCA1
germline mutation is a negative prognostic feature
and that BRCA1-related breast carcinoma has a similar or worse prognosis than age- and stage-matched
controls.9 –11 Eisinger et al. point out in their letter
that, as the prognosis for patients with medullary carcinoma might be better than that for patients with
other types of breast carcinoma, one could hypothesize that estrogen receptor negative patients who have
BRCA1-related breast carcinoma with heavy lymphocytic infiltration might be distinguished as a group
with an especially favorable prognosis. This hypothesis could be tested in future prognostic studies of
BRCA1-related breast carcinoma stratified by histopathologic group.
It is suggested by Eisinger et al. that estrogen
receptor negativity (ER2) might be a more discriminating feature than progesterone receptor negativity
(PgR2) among BRCA1-related breast carcinomas.
They claim that there is support for this in our study of
steroid receptors in hereditary breast carcinoma.3
Concerning ER2 versus PgR2, we see only a slight
difference among the BRCA1-related cases: 23 of 27
ER2 cases (85%) versus 21 of 26 PgR2 cases (81%).
Because the level of receptor negativity is arbitrary, in
this context it might be more appropriate to consider
total absence of detectable receptor levels. Such a
comparison reveals that the fraction of tumors with no
detectable ER level is 7 of 27 (26%) compared with 13
of 26 (50%) for PgR. The conclusion we draw from our
material is that if there is a difference, PgR2 is a more
typical feature of BRCA1-related breast carcinoma
than ER2. This is also more logical considering the
CANCER May 15, 1999 / Volume 85 / Number 10
transactivating effect of ER-inducing expression of
PgR.12 ER2/PgR1 is an uncommon phenotype. It occurred in only 4% of 3602 consecutive cases of breast
carcinoma in southern Sweden in 197721987; most of
these patients were ages 35249 years.13 In our study,3
3 cases (11%) displayed this feature; 2 of them had ER
levels slightly under the limit for receptor positivity
(25fmol/mg protein) and PgR levels slightly over the
same limit (ER 5 17 fmol/mg protein vs. PgR 5 49
fmol/mg protein and ER 5 14 fmol/mg protein vs.
PgR 5 35 fmol/mg protein, respectively), and the third
case had an ER 5 1.9 fmol/mg protein and PgR 5 41
fmol/mg protein phenotype.
The expression of ER is low in mature breast tissue
and increases during puberty and pregnancy.14 Its role
in the development of breast carcinoma is pivotal. It
has been suggested that increased expression is a universal and early step in breast carcinoma development
and that the level of estrogen dependence decreases
during tumor progression as the tumor grows more
malignant.15 Another possibility is that ER negative
and ER positive tumors are different from the beginning and follow different pathways during tumorigenesis; ER2 tumors are associated with progesterone
receptor negativity, high nuclear grade, and somatic
p53 mutations.14 This view is supported by the finding
that ER expression in premalignant in situ lesions and
invasive cancer adjacent to each other tend to correspond. This has been observed both in breast carcinoma in general16 and in BRCA1-related cases.17 This
preinvasive ER negativity seen in BRCA1-related tumors may indicate a lack of responsiveness to antiestrogens.18 There is, however, experimental data indicating that tamoxifen may facilitate apoptosis in ER2
human cancer cell lines.19 One can only speculate
about what implications this has for the effect of tamoxifen given as chemoprevention to women with an
increased risk for breast carcinoma based on heredity.
The need for data in this field is urgent. Unfortunately,
however, there is no faster way to find out than to
continue the randomized studies that are ongoing20,21
and to initiate others in which analysis of BRCA1 and
BRCA2 is part of the study.
Johannsson OT, Idvall I, Anderson C, Borg Å, Egilsson
V, Olsson H. Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer 1997;33:
Breast Cancer Linkage Consortium. Pathology of familial
breast cancer: differences between breast cancers in carriers
of BRCA1 or BRCA2 mutations and sporadic cases. Lancet
Loman N, Johannsson O, Bendahl P-O, Borg Å, Fernö M,
Olsson H. Steroid receptors in hereditary breast carcinomas
associated with BRCA1 or BRCA2 mutations or unknown
susceptibility genes. Cancer 1998;83:310 –9.
Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, et al. Multifactorial analysis of
differences between sporadic breast cancers and cancers
involving BRCA1 and BRCA2. J Natl Cancer Inst 1998;90:
1138 – 45.
Rosen PP. Invasive mammary carcinoma. In: Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the
breast. Philadelphia: Lippincott-Raven, 1996:404 –5.
Eisinger F, Jacquemier J, Carpin C, Stopaa-Lyonnet D, Bressac-de Paillierets B, Peyrat JP, et al. Mutations at BRCA1: the
medullary breast carcinoma revisited. Cancer Res 1998;58:
1588 –92.
Marcus JN, Watson P, Page DL, Narod SA, Lenoir GM, Tonin
P, et al. Hereditary breast cancer pathobiology, prognosis,
and BRCA1 and BRCA2 gene linkage. Cancer 1996;77:697–
Porter DE, Dixon M, Smyth E, Steel CM. Breast cancer
survival in BRCA1 carriers. Lancet 1993;341:184 –5.
Foulkes W, Wong N, Brunet J, Begin L, Zhang J, Martinez J,
et al. Germ-line BRCA1 mutation is an adverse prognostic
factor in Ashkenazi Jewish women with breast cancer. Clin
Cancer Res 1997;3:2465–9.
Ansquer Y, Gauthier C, Fourquet A, Asselain B, StoppaLyonnet D, Group ICBC. Survival in early-onset BRCA1
breast cancer patients. Lancet 1998;352:541.
Johannsson OT, Ranstam J, Borg Å, Olsson H. Survival of
BRCA1 breast and ovarian cancer patients: a populationbased study from southern Sweden. J Clin Oncol 1998;16:
397– 404.
Encarnacion CA, Fuqua SAW. Estrogen receptor variants
in breast cancer. In: Dickson R, Lippman M, editors.
Mammary tumorigenesis and malignant progression:
Dordrecht, The Netherlands: Kluwer Academic Publishers, 1994;97–109.
Fernö M, Borg Å, Johansson U, Norgren A, Olsson H, Rydén
S, et al. Estrogen and progesterone receptor analyses in
more than 4000 human breast camcer samples. Acta Oncol
1990;29:129 –35.
Habel LA, Stanford JL. Hormone receptors and breast cancer. Epidemiol Rev 1993;15:209 –19.
Moolgavkar S, Day N, Stevens R. Two-stage model for carcinogenesis: epidemiology of breast cancer in females.
J Natl Cancer Inst 1980;65:559 – 69.
Khan SA, Rogers MAM, Khurana KK, Meguid MM, Numann PJ.
Estrogen receptor expression in benign breast epithelium and
breast cancer risk. J Natl Cancer Inst 1998;90:37–42.
Osin P, Crook T, Powles T, Peto J, Gusterson B. Hormone
status of in-situ cancer in BRCA1 and BRCA2 mutation
carriers. Lancet 1998;351:1487.
Osin P, Gusterson B, Philp E, Waller J, Bartek J, Peto J, et al.
Predicted anti-oestrogen resistance in BRCA-associated familial breast cancers. Eur J Cancer 1998;34:1683– 6.
Ferlini C, Scambia G, Marone M, Distefano M, Gaggini C,
Ferrandina G, et al. Tamoxifen induces oxidative stress and
apoptosis in oestrogen receptor–negative human cancer cell
lines. Br J Cancer 1999;79:257– 63.
Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M,
et al. Interim analysis of the incidence of breast cancer in
the Royal Marsden Hospital tamoxifen randomized chemoprevention trial. Lancet 1998;352:98 –101.
21. Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C,
Robertson C, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial
among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 1998;352:93–7.
Niklas Loman, M.D.
Oskar Johannsson, M.D., Ph.D.
Pär-Ola Bendahl, Ph.D.
Åke Borg, Ph.D.
Mårten Fernö, Ph.D.
Håkan Olsson, M.D., Ph.D.
Jubileum Institute
Department of Oncology
University Hospital
Lund, Sweden
Mobilization, Collection, and
Characterization of Peripheral
Blood Hemopoietic Progenitors
after Chemotherapy with Epirubicin,
Paclitaxel, and Granulocyte-Colony
Stimulating Factor Administered to
Patients with Metastatic Breast
n a recent article published in Cancer, Bengala et al.1
reported on the capacity of a paclitaxel and epirubicin combination plus granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic progenitor cells (PBPCs) in the circulation. This article is of
relevant clinical interest because the anthracycline/
paclitaxel combination is used widely as induction
therapy before high dose regimens in metastatic
breast carcinoma patients. Quite unexpectedly, the
authors did not mention in the article what to our
knowledge is the only previous report, from our institution, dealing with the same issue.2 We believe the
comparison between their results and our may have
raised some interesting questions. Although leukapheresis was performed after the first chemotherapy
administration in the majority of cases, in our study
the mean number of CD341 cells collected was lower
(3.7 3 106/kg vs. 6.3 3 106/kg) than reported by Bengala et al. This discrepancy can be explained in part by
the different dose of paclitaxel used in the two studies
(135 mg vs. 200 mg). However, in a more recent unpublished series of 20 patients from our institution
with metastatic breast carcinoma, the mean number
of CD341 cells collected after the fourth cycle of epirubicin (90 mg/m2) and paclitaxel (175 mg/m2) plus
G-CSF again was lower than reported by Bengala et al.
(4.6 3 106/kg vs 6.3 3 106/kg). We believe that the lack
of standardization of CD34 quantification assays may,
as in this case, hamper the direct comparison of published reports. This problem often has been raised3,4
by societies operating in this field but to our knowledge never actually solved despite the encouraging
efforts of the ISHAGE.5 Recently, Serke et al.6 showed
that technical differences among laboratories in enumerating progenitor cells (colony-forming unit-granulocyte macrophage and CD341) may make a major
contribution to the clinical variability observed after
transplantation of subthreshold progenitor cell dose.
This is not the case in the report of Bengala et al.
because their patients received a high number of
PBPCs after high dose chemotherapy but, again, this
issue will have to be investigated further.
Based on their results regarding CD341/CD332
and CD341/CD382 cells in the leukapheretic products, Bengala et al. suggest that epirubicin and paclitaxel are not toxic for very primitive hematopoietic
progenitors but this statement is not clearly supported
by the data presented. The number of more immature
progenitors reported in this article is by far inferior to
previous studies7,8 and, more important, the mobilization of CD341/CD332 cells in patients who had
received $ six cycles (data on the CD341/CD382
subset are not shown) is reduced greatly when compared with less treated subjects. It would has been
interesting to know, given the wide range of CD341/
CD332 cells reinfused, if there was a correlation between the amount of this cell population present in
the graft and the kinetic of engraftment. Pecora et al.
recently have reported that CD341/CD332 cells significantly influence engraftment kinetics and transfusion requirements in autologous blood stem cell recipients.9 Along with immunophenotyping studies we
believe that the functional quantitation of long term
culture initiating cells (LTC-IC or CAFC) may help in
understanding the role of primitive progenitors
present in the graft.
Bengala C, Pazzagli I, Tibaldi C, Favre C, Vanacore R, Greco
F, et al. Mobilization, collection, and characterization of
peripheral blood hemopoietic progenitors after chemotherapy with epirubicin, paclitaxel, and granulocyte-colony
stimulating factor administered to patients with metastatic
breast carcinoma. Cancer 1998;82:867–73.
Pedrazzoli P, Perotti C, Da Prada GA, Bertolini F, Gibelli N,
Torretta L, et al. Collection of circulating progenitor cells
after epirubicin, paclitaxel and filgrastim in patients with
metastatic breast cancer. Br J Cancer 1997;75:1368 –72.
CANCER May, 15 1999 / Volume 85 / Number 10
Wunder E, Sovalat H, Fritsch G, Silvestri F, Henon P, Serke
S. Report on the European Workshop on peripheral blood
stem cell determination and standardization. J Hematother
1992;1:131– 42.
Johnsen HE. Toward a worldwide standard for CD341 enumeration? J Hematother 1996;6:83–9.
Keeney M, Chin-Yee I, Weir K, Popma J, Nayar R, Sutherland
DR. Single platform flow cytometric absolute CD341 cell
counts based in the ISHAGE guidelines. Cytometry 1998;34:
Serke S, Arseniev L, Watts M, Fritsch G, Ingles-Esteve J,
Johnsen HE, et al. Imprecision in counting CFU-GM colonies and CD34-expressing cells. Bone Marrow Transplant
1997;20:57– 61.
To LB, Haylock DN, Dowse T, Simmons PJ, Trimboli S,
Ashman LK, et al. A comparative study of the phenotype and
proliferative capacity of peripheral blood (PB) CD341 cells
mobilized by four different protocols and those of steadyphase PB and bone marrow CD341 cells. Blood 1994;84:
2930 –9.
Tyonnfijord GE, Steen R, Evensen SA, Thorsby E, Egeland T.
Characterization of CD341 peripheral blood cells from
healthy adults mobilized by recombinant human granulocyte colony-stimulating factor. Blood 1994;84:2795– 801.
Pecora AL, Preti RA, Gleim GW, Jennis A, Zahos K, Cantwell
S, et al. CD341CD332 cells influence days to engraftment
and transfusion requirement in autologous blood stem-cell
recipients. J Clin Oncol 1998;16:2093–104.
Paolo Pedrazzoli, M.D.
Luisa Ponchio, M.D.
Carlo Zibera, M.D.
Gian Antonio Da Prada, M.D.
Gioacchino Robustelli della Cuna, M.D.
Divisione di Oncologia Medica
Fondazione S. Maugeri
Pavia, Italy
Author Reply
n their letter Pedrazzoli et al. raise some very interesting issues. We agree that it is difficult to compare
numbers of CD341 cells collected in different institutions because CD341 quantification assays are not
standardized. This may explain the discrepancy between their results1 and ours.2
Of concern is the possibility of collecting very
primitive hemopoietic progenitors after priming with
paclitaxel, epirubicin and granulocyte-colony stimulating factor (G-CSF). We know that the lack of CD33
and CD38 antigen expression identifies earlier hemopoietic progenitors.3,4 In our study3 we performed a
phenotypic characterization of collected mononuclear
cells and found that the mean percentage of CD341/
CD332 and CD341/CD382 cells were 0.8% and
0.11%, respectively, and the mean numbers of
CD341/CD332 and CD341/CD382 cells/kg per leukapheresis were 2 3 106 and 0.18 3 106, respectively.
Again we believe that it is difficult to compare data
from CD341/CD332 and CD341/CD382 cell mobilization performed in different institutions because of
the lack of standardization of quantification assays
and because of the different characteristics of the patients. All our patients were pretreated with chemotherapy (as adjuvant treatment and for metastatic disease) and we know that repetitive courses of treatment
may affect the mobilization of hemopoietic progenitors negatively, mainly the most primitive ones.5 Our
data2 also are in agreement with those of Pedrazzoli et
al.1 showing the possibility of collecting more primitive hemopoietic progenitors after paclitaxel, epirubicin, and G-CSF. They showed, in a very elegant fashion, that cobblestone area-forming cells are present in
the leukapheresis product. This long term colony assay is believed to be the best surrogate for early progenitor cell enumeration. The mobilization of these
very primitive hemopoietic progenitors into the peripheral blood indirectly may support the hypothesis
that the combination of paclitaxel and epirubicin may
be not toxic for very early hemopoietic progenitors.
Pedrazzoli P, Perotti C, Da Prada GA, Bertolini F, Gibelli N,
Torretta L, et al. Collection of circulating progenitor cells
after epirubicin, paclitaxel and filgrastim in patients with
metastatic breast cancer. Br J Cancer 1997;75:1368 –72.
Bengala C, Pazzagli I, Tibaldi C, Favre C, Vanacore R, Greco
F, et al. Mobilization, collection, and characterization of
peripheral blood hemopoietic progenitors after chemotherapy with epirubicin, paclitaxel, and granulocyte-colony
stimulating factor administered to patients with metastatic
breast carcinoma. Cancer 1998;82:867–73.
Bernstein ID, Leary AG, Andrews RG, Singer JW, Bryant EM,
Bartelmez SH, et al. Blast colony-forming cells and precursors of colony-forming cells detectable in long-term marrow
culture express the same phenothype (CD332CD341). Exp
Hematol 1991;19:680 –2.
Terstappen LWMM, Huang S, Safford M, Lansdorp PM,
Loken MR. Sequential generations of hematopoietic colonies derived from single nonlineage-committed CD341CD382progenitor cells. Blood 1991;77:1218–27.
Baumann I, Swindell R, Van Hoeff MEHM, Dexter TM, de
Wynter E, Lange C, et al. Mobilisation kinetics of primitive
haemopoietic cells following G-CSF with or without chemotherapy for advanced breast cancer. Ann Oncol 1996;7:
Carmelo Bengala, M.D.
Pier Franco Conte, M.D.
Division of Medical Oncology
St. Chiara Hospital
Pisa, Italy
Computed Tomography Analysis of
Causes of Local Failure in
Radiotherapy for Cervical
certainly enjoyed “Computed Tomography Analysis
of Causes of Local Failure in Radiotherapy for Cervical Carcinoma” by Suyama et al.,1 which updated
some of the same arguments made by Durrance,
Fletcher, and Rutledge2 3 decades ago. According to
the classic article by Durrance, “In the bulky expansile
lesion of the endocervix, tumor cells deep in the myometrium are beyond the zone of adequate dosage
because of the pear-shaped isodose distribution of the
vaginal and intrauterine radium.” Intracavitary radiation, like all forms of radiation, cannot cure what is
missed because of underdosage.
Although I wholeheartedly agree that to prescribe
to point A when the gross target volume is beyond
point A makes little sense, I have some concerns about
the analysis of Suyama et al. First, the most obvious
source of bias in the analysis is that the largest tumors
after external radiation therapy are apt to be the most
radioresistant, and thus the biology of the tumor as
well as the physics of the brachytherapy would be
unfavorable. It is hard for the reader to decide whether
these patients are failing because these are the worst
tumors or because they receive the lowest minimum
peripheral dose. A distinct advantage of this series is
that the patients were treated according to the protocol of Arai et al.,3 and the brachytherapy prescription
did not change according to the response. Because we
wish to see the impact of the brachytherapy dose, why
not statistically correct for size of the residual tumor at
the time of brachytherapy, and then determine the
relation between minimum peripheral brachytherapy
dose to local control?
The authors have apparently surmounted some
technical barriers, and I would ask them to clarify their
methods. Was general anesthesia used in the placement of the intrauterine applicators? If so, was the
same anesthesia and packing employed prior to the
insertion of the computed tomography (CT) opaque
plastic applicators? Perhaps the plastic applicators
were used for treatment as well as for CT image acquisition. A plastic applicator that could be used for
CT treatment planning as well as treatment would be
a huge advance.
I join with the authors in the hope that with better
technology we can make the leap from talking about
the area of the cervix (determined by considering four
or five CT slices per patient per cervix and choosing
the largest one) to considering the macroscopic target
Suyama S, Nakaguchi T, Kawakami K, Shou K, Fushiki M,
Taneike M, et al. Computed tomography analysis of causes
of local failure in radiotherapy for cervical carcinoma. Cancer 1998;83:1956 – 65.
Durrance FY, Fletcher GH, Rutledge FN. Analysis of central
recurrent disease in stages I and II squamous cell carcinomas of the cervix on intact uterus. Am J Roentgenol Radium
Ther Nucl Med 1969;106:831– 8.
Arai T, Nakano T, Morita S, Sakashita K, Nakamura YK,
Fukuhisa K. High-dose-rate afterloading intracavitary radiation therapy for cancer of the uterine cervix. Cancer 1992;
69:175– 80.
Jonathan J. Beitler, M.D., M.B.A.
Departments of Radiation Oncology and
Montefiore Medical Center
Bronx, New York
Author Reply
e appreciate the interest of Dr. Beitler in our
article.1 As indicated in that article, several authors have noted that local tumor control and 5-year
survival rates decrease with tumor volume. It is generally accepted that the level of brachytherapy doses
at the periphery of tumors is lower in larger tumors,
and this relation influences local tumor control and
5-year rates of survival. In addition, there is no evidence showing tumor radioresistance in relation to
cervical tumor volume, such as hypoxic tumor cell
fraction increasing with the tumor volume.
However, in the manner suggested by Dr. Beitler
(as we are also interested in whether radiosensitivity is
affected by tumor volume of cervical carcinoma), we
conducted a further analysis of our patient series. We
divided our patients into 3 groups according to the
cervical area and minimum percent dose, i.e., 1) cervical area of less than 15 cm2 and minimum percent
dose of less than 60%, 2) cervical area of less than 15
cm2 and minimum percent dose of greater than 60%,
and 3) cervical area of more than 20 cm2 and minimum percent dose of less than 60%.
In these 3 groups, the local tumor control rates for
Groups 1, 2, and 3 were 45.5% (5/11), 88.4% (38/43),
and 33.3% (4/12), respectively. There was a significant
difference in the local tumor control rate between
CANCER May, 15 1999 / Volume 85 / Number 10
Groups 1 and 2 (Fisher exact test; P 5 0.005), but not
between Groups 1 and 3 (Fisher exact test; P 5 0.680).
These findings indicate that the local tumor control rate depends on the minimum percent dose
among patients with the same size cervical area and
that when the cervical area differs among the patients
receiving the same minimum percent dose, the local
tumor control rate will be similar.
Our analysis indicates that radiosensitivity is not
altered by tumor volume and that minimum percent
dose is the most important factor in local tumor control. Dr. Beitler also suggested that we statistically
correct for tumor size after brachytherapy. However,
we did not do so because we only wanted to clarify the
relation between the brachytherapy dose and the ultimate radiotherapy endpoint of local tumor control.
We were not concerned with temporary tumor response. Finally, we did not use general anesthesia
during the application of tandem and ovoids applicators, computed tomography image acquisition, or
brachytherapy treatments.
Suyama S, Nakaguchi T, Kawakami K, Shou K, Fushiki M,
Taneike M, et al. Computed tomography analysis of causes
of local failure in radiotherapy for cervical carcinoma. Cancer 1998;83:1956 – 65.
Sumio Suyama, M.D.
Takahiro Nakaguchi, M.D.
Kouichi Kawakami, M.D.
Keizen Shou, M.D.
Masato Fushiki, M.D.
Makoto Taneike, M.D.
Akira Matsui, M.D.
Masasi Takahashi, M.D.
Rikushi Morita, M.D.
Department of Radiology
Shiga University of Medical Science
Otsu, Shiga, Japan
Hemophagocytic Syndrome in Five
Patients with Epstein–Barr Virus
Negative B-Cell Lymphoma
n the recent publication on B-cell proliferation-associated hemophagocytic syndrome (B-LAHS), Ohno et
al.1 hypothesized that neoplastic Epstein–Barr virus
(EBV) free B-cells may play the same role as EBV-infected neoplastic T-cells in peripheral T-cell lymphoma
(PTCL) as well intervening nonneoplastic T-cells. To our
knowledge, to date hemophagocytosis associated with
hypercytokinemia mainly has been documented in hemophagocytic lymphohistiocytosis (HLH) in childhood
and/or PTCL in adults. Although data were very limited
regarding B-LAHS, a comparative study on serum cytokine patterns between T-cell proliferation-associated hemophagocytic syndrome (T-LAHS) and B-LAHS may be
useful in understanding the pathogenesis of lymphoproliferative disease-related hemophagocytosis. We compared the serum cytokine levels between clonal T-LAHS
and B-LAHS.
Sera were obtained from 14 patients with pediatric HLH with a median age of 2 years (range, 0.5–17
years) and a male/female ratio of 5/9. All patients met
the diagnostic criteria of HLH and were confirmed to
show clonal rearranged bands in either of the T-cell
receptor b-, g-, or d-chains by Southern blot analysis
using DNA extracted from peripheral blood mononuclear cells or bone marrow cells at the active phase of
the disease. Surface marker studies of these cells were
T-cell dominant. Serum interferon-g (IFN-g), interleukin-6 (IL-6), and soluble IL-2 receptor (sIL-2R) were
determined as described previously.2,3 With regard to
B-LAHS cases, we collected seven cases from the literature in which the values of these three cytokines
were available, having been determined using the
same methods as our cases.4 –7 These patients all were
adults with a median age of 61 years (range, 44 – 84
years). Data were compared between the two groups
using the Student t test.
Median values and ranges were as follows in the
T-LAHS cases: IFN-g: median, 123 U/mL and range,
3.0 –1,000 U/mL; sIL-2R: median: 23,300 U/mL and
range, 11,400 – 60,000 U/mL and IL-6: median, 70.4
pg/mL and range, 9.0 –19,400 pg/mL. The median values and ranges in the B-LAHS cases were as follows:
IFN-g: median, 1.0 U/mL and range, 0.7–15.5 U/mL;
sIL-2R: median, 15,250 U/mL and range, 8290 –22,200
U/mL; and IL-6: median, 38.2 pg/mL and range, 9.4 –
87.3 pg/mL. As shown in Figure 1 serum concentrations of IFN-g in the T-LAHS cases were two log
greater (P 5 0.005) than those in B-LAHS, whereas the
sIL-2R and IL-6 concentrations were not significantly
different between the two groups. With regard to EBV
involvement, 11 of the 14 T-LAHS cases were identified as EBV positive whereas none of the B-LAHS cases
was reported to be EBV-related.
The most striking finding was the magnitude of
increased IFN-g in T-LAHS cases. In the data by Ohno
et al.1 examining 5 cases of B-LAHS, sIL-2R levels
(median, 17,200 U/mL and range, 8460 –31,000 U/mL)
and IL-6 levels (median, 128 pg/mL and range, 23–202
pg/mL) were comparable to ours; however, their
IFN-g values (median, 24.7 pg/mL range, 13.8 –19.1
FIGURE 1. Serum concentrations of 14 hemophagocytic lymphohistiocytosis
cases (all of which showed clonal T-cell proliferation-associated hemophagocytic syndrome [T]) and 7 B-cell proliferation-associated hemophagocytic
syndrome (B) cases are compared. Columns indicate mean 6 standard
deviations (bars) and asterisks indicate the median. Interferon-g (IFN-g) is
presented as original scale and soluble interleukin-2 receptor (sIL-2R) in 1022
and IL-6 in 1021 scales. A statistically significant difference (P 5 0.005) was
noted only with IFN-g.
pg/mL; normal, , 7.8 pg/mL) appeared to show a
mild increase but we were not able to compare them
with our reported values due to the different assay
system employed.
These results clearly indicate that the cells expressing sIL-2R must be involved in the pathogenesis
of hemophagocytosis in both groups; however, IFN-g
appears to have a more significant impact in T-LAHS,
suggesting that clonally transformed T-cells synthesize and secrete enormous amounts of this cytokine
under unregulated and EBV-influenced conditions. In
B-LAHS, data may confirm the hypothesis by Ohno et
al.1 that reactively activated mature T-cells, in response to a specific type of B-lymphoma or to intervening viral infections, secrete IFN-g, which activates
macrophages resulting in hemophagocytosis similar
to T-LAHS. Although age differences and other cytokine levels also must be considered, the precise evaluation of clinical features caused by the significantly
different serum IFN-g concentrations remains to be
determined between T-LAHS and B-LAHS.
Ohno T, Miyake N, Hada S, Hirose Y, Imura A, Hori T, et al.
Hemophagocytic syndrome in five patients with Epstein–
Barr virus negative B-cell lymphoma. Cancer 1998;82:1963–
Imashuku S, Hibi S, Fujiwara F, Ikushima S, Todo S. Haemophagocytic lymphohistiocytosis, interferon-gamma-naemia and Epstein-Barr virus involvement. Br J Haematol
1994;88:656 – 8.
Imashuku S, Hibi S, Fujiwara F, Todo S. Hyper-interleu-
kin(IL)-6-naemia in haemophagocytic lymphohistiocytosis.
Br J Haematol 1996;93:803–7.
Suzuki T, Nonaka Y, Hayashi T, Nomura T, Ogawa M, Mori
S. Diffuse B-cell lymphoma associated with hemophagocytic syndrome. Jpn J Clin Hematol 1998;39:59 – 65.
Murase T, Nakamura S, Tashiro K, Suchi T, Hiraga J, Hayasaki N, et al. Malignant histiocytosis-like B-cell lymphoma, a distinct pathologic variant of intravascular lymphomatosis: a report of five cases and review of the
literature. Br J Haematol 1997;99:656 – 64.
Yamada K, Katoh K, Okuyama M. Diffuse B-cell lymphoma
associated with hemophagocytic syndrome. Jpn J Clin Hematol 1996;37:161– 4.
Miyahara M, Nakano H, Shimoda M, Funai N, Watanabe M,
Shibata K, et al. PBSCT for NHL with hypercytokinemia and
phagocytic syndrome [abstract]. Int J Hematol 1995;
Shinsaku Imashuku, M.D.
Shigeyoshi Hibi, M.D.
Yasuhiro Tabata, M.D.
Shinjiro Todo, M.D.
Division of Pediatrics
Children’s Research Hospital
Department of Pediatrics
Kyoto Prefectural University of Medicine
Kyoto, Japan
Author Reply
e read with great interest the letter by Imashuku
et al. regarding our recent description of hemophagocytic syndrome with Epstein–Barr virus
(EBV) negative B-cell lymphomas.1 Although we could
not differentiate the pattern of hypercytokinemia
among the data in our hands, Imashuku et al. observed significantly higher levels of serum interferon-g
(IFN-g) concentrations in T-cell lymphoma-associated hemophagocytic syndrome (T-LAHS) when compared with B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS). The result was extracted
from the huge accumulation of their data regarding
hemophagocytic syndrome (HPS).2– 4 The majority of
their T-LAHS cases were EBV-related, whereas
B-LAHS cases were not. Although we should be careful
concerning the age difference, their observation provides an important clue in understanding the difference in the pathogenesis of HPS between T-LAHS and
In B-LAHS cases, as well as angioimmunoblastic
lymphadenopathy with dysproteinemia and pleomorphic T-cell lymphoma of angioinvasive type in
T-LAHS, a histologic predisposition may exist. The
majority of histologically proven cases are intravascu-
CANCER May, 15 1999 / Volume 85 / Number 10
lar lymphomatosis.1,5 These are followed by T-cell rich
B-cell lymphomas and those simply documented as
diffuse large cell type. Thus, nearly all B-LAHS cases
are considered to constitute a unique subtype of diffuse large B-cell lymphomas. It is interesting to note
that, in this subtype, many reactive cells, including
lymphocytes, histiocytes, and endothelial cells, are intermingled with systemically disseminated but relatively few neoplastic cells. In such a case, hypercytokinemia in B-LAHS may not be ascribed to the
neoplastic cells themselves. Conversely, interleukin
(IL)-2 and IL-6 are well known to be B-cell helper
factors that also are elaborated by B cells themselves.
Although INF-g may exhibit some helper activity and
delay apoptosis of CD5 positive chronic lymphocytic
leukemia cells, evidence that B cells produce IFN-g
has not been accumulated.6,7 Thus, we assume that
intervening, reactively activated, nonneoplastic T cells
may be responsible for the induction of B-LAHS, in
which the magnitude of increased INF-g is relatively
low compared with T-LAHS, as Imashuku et al. have
Ohno T, Miyake N, Hada S, Hirose Y, Imura A, Hori T, et al.
Hemophagocytic syndrome in five patients with EpsteinBarr virus negative B-cell lymphoma. Cancer 1998;82:1963–
Imashuku S, Ikushima S, Etsumi N, Todo S, Saito M. Serum
levels of interferon gamma, cytotoxic factor and soluble
interleukin-2 receptor in childhood hemophagocytic syndromes. Leuk Lymphoma 1991;3:287–92.
Imashuku S, Hibi S, Fujiwara F, Ikushima S, Todo S. Haemophagocytic lymphohistiocytosis, interferon-gamma-naemia and Epstein-Barr virus involvement. Br J Haematol
1994;88:656 – 8.
Imashuku S, Hibi S, Fujiwara F, Todo S. Hyper-interleukin
(IL)-6-naemia in hemophagocytic lymphohistiocytosis. Br J
Haematol 1996;93:803–7.
Murase T, Nakamura S, Tashiro K, Suchi T, Hiraga J, Hayasaki N, et al. Malignant histiocytosis-like B-cell lymphoma, a distinct pathologic variant of intravascular lymphomatosis: a report of five cases and review of the
literature. Br J Haematol 1997;99:656 – 64.
Buschle M, Campana D, Carding SR, Richard C, Hoffbrand
AV, Brenner MK. Interferon gamma inhibits apoptotic cell
death in B cell chronic lymphocytic leukemia. J Exp Med
1993;177:213– 8.
Young HA. Regulation of interferon-gamma gene expression. J Interferon Res 1996;16:563– 8.
Tatsuharu Ohno, M.D.
Division of Hematology
and Immunology
Department of Internal Medicine
Ohtsu Red Cross Hospital
Shiga, Japan
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