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238
CORRESPONDENCE
The Prognostic Significance of Amplification
and Overexpression of c-met and c-erb B-2
in Human Gastric Carcinomas
he article by Nakajima et al.1 reports very interesting findings on
the putative prognostic meaning of the amplification and overexpression of c-met and c-erb B-2 in patients with gastric carcinoma.
The finding of a significant correlation between gene amplification/overexpression of c-erb B-2 with the intestinal type of gastric
carcinoma corresponds with our own results on the same topic.2
In our hands, like in the study by Nakajima et al., c-met amplification/overexpression tends to be higher in diffuse carcinoma
whereas c-erb B-2 amplification/overexpression is restricted almost
exclusively to intestinal type carcinoma.2,3
The data from Nakajima et al.1 also demonstrate the advantage
of the classification of Laurén over the World Health Organization
(WHO) classification because Laurén’s classification divides gastric
carcinoma into two major types with epidemiologic and histogenetic meaning. The separation of gastric carcinoma into these two
main types also contributes to clarification of the problem of
grading because the majority of the so-called poorly differentiated
carcinomas fit into the category of intestinal carcinoma (and often
display c-erb B-2 amplification/overexpression) rather than into
the category of diffuse carcinoma. This option is reinforced by the
finding of a close correlation between E-cadherin mutation and
diffuse carcinoma,4 both in pure histologic types as well as in
mixed carcinoma. In the latter, E-cadherin mutations are found in
the isolated cell component and not in the glandular counterpart.4
With regard to prognosis our data also fit with those of Nakajima
et al.1 by showing the prominence of staging5,6 and the lack of relative
importance of histologic classification whenever the Laurén or WHO
classifications are used.5 The same does not hold true when the
tumors are classified into four major categories: glandular, isolated
cell type, mixed, and solid.5 This classification was found to carry
independent prognostic value in multivariate analysis mainly due to
the dismal outcome of patients with mixed carcinomas.5
It would be interesting to know whether, in the series by Nakajima et al.,1 c-met and c-erb B-2 amplification/overexpression differs,
like E-cadherin mutations, in the two components of mixed carcinomas. It also would be interesting to learn if such mixed carcinomas in
the series by Nakajima et al. carry a worse prognosis than pure
histologic types, as they did in our study.
T
REFERENCES
1.
2.
© 2000 American Cancer Society
Nakajima M, Sawada H, Yamada Y, Watanabe A, Tatsumi M, Yamashita J, et al.
The prognostic significance of amplification and overexpression of c-met and
c-erb B-2 in human gastric carcinomas. Cancer 1999;85:1894 –902.
David L, Seruca R, Nesland JM, Soares P, Sansonetty F, Holm R, et al. C-erb
239
3.
4.
5.
6.
B-2 expression in primary gastric carcinomas and their
metastases. Mod Pathol 1992;5:384 –90.
Seruca R, Suijkerbuijk RF, Gartner F, Criado B, Veiga I,
Olde-Weghuis D, et al. Increasing levels of MYC and MET
co-amplification during tumor progression of a case of gastric cancer. Cancer Genet Cytogenet 1995;82:140 –5.
Machado JC, Soares P, Carneiro F, Rocha A, Beck S, Blin N,
et al. E-cadherin gene mutations provide a genetic basis for
the phenotypic divergence of mixed gastric carcinomas. Lab
Invest 1999;79:459 – 65.
Carneiro F, Seixas M, Sobrinho-Simões M. New elements for
an updated classification of the carcinomas of the stomach.
Pathol Res Pract 1995;191:571– 84.
Amado M, Carneiro F, Seixas M, Clausen H, SobrinhoSimões M. Dimeric sialyl-Lex expression in gastric carcinoma correlates with venous invasion and poor outcome.
Gastroenterology 1998;114:462–70.
Fátima Carneiro, M.D., Ph.D.
Manuel Sobrinho-Simões, M.D., Ph.D.
Institute of Molecular Pathology
and Immunology
University of Porto (IPATIMUP)
Medical Faculty of Porto
Porto, Portugal
Author Reply
W
e appreciate the comments by Drs. Carneiro
and Sobrinho-Simoes regarding our article.
We are interested in their histologic classification
of gastric carcinoma,1 which was found to carry
independent prognostic value in multivariate analysis, appearing as the second most important prognostic factor (after TNM staging) in patients with
gastric carcinoma. Carneiro et al. divided gastric
FIGURE 1.
Survival curves of 128 patients with four different types of
gastric carcinoma according to the classification of Carneiro et al. A:
glandular carcinoma (n 5 43); B: isolated cell carcinoma (n 5 25); C: solid
carcinoma (n 5 8); and D: mixed carcinoma (n 5 52). There was no
significant correlation between the four different types of gastric carcinoma
and the survival rate.
carcinomas into four major categories: glandular,
isolated cell type, solid, and mixed. Therefore we
reexamined our data according to their classification.
Of the total of 128 cases, 43 (33.6%) showed
glandular carcinoma, 25 (19.5%) showed isolated
cell carcinoma, 8 (6.3%) showed solid carcinoma,
and 52 (40.6%) showed mixed carcinoma. There
was no significant correlation between any of the
four different types of gastric carcinoma and the
survival rate (Fig. 1). In univariate analysis, the rate
of c-met overexpression in glandular carcinoma
was significantly lower than that of the other types
of carcinoma and there was a significant correla-
TABLE 1
Correlation of c-met/c-erb B-2 Gene Amplification and Overexpression with Histologic Type According to the Classification of Carneiro et al.
using Univariate Analysis
c-met
Gene amplification
Variables
No. of
cases
No.
amplified
Histologic type according to the classification of
Carneiro et al.
Glandular carcinoma
Isolated cell carcinoma
Solid carcinoma
Mixed carcinoma
43
25
8
52
2
3
2
6
a
Calculated by the chi-square test (glandular carcinoma vs. other type carcinoma).
c-erb B-2
Overexpression
P valuea
No. positive
P valuea
0.25
12
11
7
29
0.006
Gene amplification
No.
amplified
10
1
0
4
P valuea
0.009
Overexpression
No.
positive
13
1
1
6
P valuea
0.006
240
CANCER January 1, 2000 / Volume 88 / Number 1
Amado et al.2,3 It is clear that these factors ( c-erb
B-2, c-met, E-cadherin, and Sialyl-Lex) correlate
with histopathologic type in gastric carcinoma and
influence prognosis.
TABLE 2
Multivariate Analysis of Predictive Prognostic Factors
P value
Prognostic factors
c-met only
c-erb B-2 only
c-met and
c-erb B-2
Overexpression of c-met
Overexpression of c-erb B-2
Coexpression of both c-met
and c-erb B-2
Depth of invasion
Carneiro et al. classification
Stromal type
Lymph node metastasis
Lymphatic invasion
Vascular invasion
0.0006
—
—
0.0253
—
—
—
0.5034
0.7949
0.0344
0.0045
0.0839
0.8589
—
0.6783
0.201
0.5782
0.0026
0.2104
0.1356
0.0038
0.9545
0.2945
0.4565
0.0011
0.1659
0.4234
REFERENCES
1.
2.
3.
4.
tion between gene amplification/overexpression of
c-erb B-2 and glandular carcinoma (Table 1). In
52 cases of mixed carcinoma, only 6 showed overexpression of c-erb B-2 and mainly their glandular
component was stained. Multivariate analysis was
performed using the following covariates that
showed statistical significance in the univariate
analysis: depth of tumor invasion (advanced vs.
early), histologic type according to the classification
of Carneiro et al. (glandular vs. the other types),
stromal type (scirrhous vs. nonscirrhous), lymph
node metastasis (positive or negative), lymphatic
invasion (positive or negative), venous invasion
(positive or negative), and c-met or c-erb B-2 overexpression (positive or negative). The results of
the multivariate analysis showed that c-met or c-erb
B-2 overexpression or coexpression of both c-met
and c-erb B-2 and lymph node metastasis were
independent prognostic factors for poor outcome
(Table 2).
Machado et al. reported that E-cadherin mutation was correlated with diffuse carcinoma as well
as the diffuse component of mixed tumors.2 Amado
et al. reported the correlation between Sialyl-Lex
and mixed type gastric carcinomas.3 There was a
significant correlation between these factors and
histologic type using the classification system of
Carneiro et al.1 Previously, we reported4 that decreased E-cadherin expression frequently was
detected in undifferentiated type gastric carcinoma and correlated with shorter patient survival
after curative surgery regardless of stage of disease. Moreover, we also reported5 that expression
of Sialyl-Lex correlated significantly with the histologic differentiation of gastric carcinoma and synchronous and/or metachronous liver metastasis.
Our results nearly fit those of Machado et al. and
5.
Carneiro F, Seixas M, Sobrinho-Simoes M. New elements for
an updated classification of the carcinomas of the stomach.
Pathol Res Pract 1995;191:571– 84.
Machado JC, Soares P, Carneiro F, Rocha A, Bech S, Blin N,
et al. E-cadherin gene mutations provide a genetic basis for
the phenotypic divergence of mixed gastric carcinomas. Lab
Invest 1999;79:459 – 65.
Amado M, Carneiro F, Seixas M, Clausen H, Sobrinho-Simoes M. Dimeric sialyl-Lex expression in gastric carcinoma
correlates with venous invasion and poor outcome. Gastroenterology 1998;114:462–70.
Sino Y, Watanabe A, Yamada Y, Tanase M, Yamada T, Matsuda M, et al. Clinicopathological evaluation of immunohistochemical E-cadherin expression in human gastric carcinomas. Cancer 1995;76:2193–201.
Tastumi M, Watanabe A, Sawada H, Yamada Y, Sino Y,
Nakano H. Immunohistochemical expression of the sialyl
Lewis x antigen on gastric cancer cells correlates with the
presence of liver metastasis. Clin Exp Metastasis 1998;16:
743–50.
Masakazu Nakajima, M.D.
First Department of Surgery
Nara Medical University
Nara, Japan
Extramedullary Plasmacytoma:
Tumor Occurrence and Therapeutic
Concepts
I
read with interest the report of Alexiou et al. on
the treatment of extramedullary plasmacytoma
(EMP), located especially in the upper aerodigestive
tract.1 The authors suggest a combination of surgery
and radiotherapy in these cases, particularly when
complete surgical tumor resection may not be possible. I do not agree with the authors. This combination is highly aggressive and may be disabling.
Plasma cell tumors are quite chemosensitive. In a
series of 35 patients with EMP, Soesan et al. reported that for 19 of them treated with initial chemotherapy, the complete response rate was 58%.2
Three patients were treated with chemotherapy only
and were alive and disease free after a minimum
follow-up of 8 years. Another case of EMP of the
urinary bladder was successfully treated with short
term oral melphalan.3 In some anatomic sites, such
as the liver, surgery and radiotherapy may be ex-
Correspondence
tremely toxic. Recently, we successfully treated a
patient with a primary extramedullary plasmacytoma (PEMP) of the liver with combination chemotherapy that consisted of vincristine, doxorubicin,
and dexamethasone (VAD). PEMP of the liver is very
rare; only four cases have been reported so far.4 –7
Two cases in the literature were treated with surgery.4 –5 The first case had received adjuvant chemotherapy with vincristine and cyclophosphamide.4
There is a third case whose treatment details are not
given.6 The fourth case is the current one, a woman
age 22 years who was found to harbor a liver plasmacytoma in July 1995. The pathology of the case
has been previously reported.7 Bone survey, bone
marrow aspiration, and biopsy were normal. Serum
immunoelectrophoresis showed immunoglobulin G
kappa type monoclonal gammopathy. Ultrasonographic examination and computed tomography of
the abdomen revealed a hepatic mass, 12 cm in
greatest dimension, which extended to both lobes.
This ruled out the possibility of surgical excision,
and radiation therapy was considered an extremely
toxic modality. VAD combination chemotherapy
was given (vincristine 0.4 mg/day by intravenous
[i.v.] continuous infusion [CI] 3 4 days; doxorubicin
9 mg/m2/day i.v. CI 3 4 days; dexamethasone 40 mg
orally on Days 1– 4, 9 –12, and 17–20 with an H2
receptor blocker, every 28 days). At the end of the
eighth cycle, all laboratory tests were within normal
ranges. However, a liver mass 7 cm in greatest dimension confined to the right lobe persisted. Thus,
segmentectomy involving the fifth, sixth, and seventh segments of the right lobe of the liver, cholecystectomy, lymph node excision, and a wedge biopsy of the right and left lobes interface were
performed. Pathology examination showed only necrosis without any residual tumoral tissue. The patient received interferon-a-2b therapy for remission
maintenance for 2 years. At her last follow-up, she
was in a fairly good condition 48 months after diagnosis and disease free for 39 months after surgery.
All physical and laboratory tests, as well as abdominal ultrasonography (except for right lobectomy),
were within normal limits.
I think induction chemotherapy is a very effective
treatment modality and should be tried primarily especially for EMP in visceral organs. By this method,
organ preservation may be possible and aggressive
therapies could be avoided, while systemic disease
control could also be provided.
REFERENCES
1.
Alexiou C, Kau RJ, Dietzfelbinger H, Kremer M, Spieß JC,
Schratzenstaller B, et al. Extramedullary plasmacytoma: tu-
2.
3.
4.
5.
6.
7.
241
mor occurrence and therapeutic concepts. Cancer 1999;85:
2305–14.
Soesan M, Paccagnella A, Chiarion-Sileni V, Salvagno L,
Fornasiero A, Sotti G, et al. Extramedullary plasmacytoma:
clinical behaviour and response to treatment. Ann Oncol
1992;3:51–7.
Matsumiya K, Kanayama Y, Yamaguchi S, Ueyama Y,
Iwasaki M, Osafune M. Extramedullary plasmacytoma
(EMP) of urinary bladder. Urology 1992;40:67–70.
Dohy A, Abe T, Takata N, et al. Successful hepatectomy for solitary plasmacytoma. N Engl J Med 1979;24:
1218 –9.
Weichhold W, Labouyrie E, Merlio JP, Masson B, de Mascarel A. Primary extramedullary plasmacytoma of the liver: a
case report. Am J Surg Pathol 1995;19:1197–202.
Suzuki N, Sakane T, Tsunematsu T, Nakamura T, Morikawa
S, Nagaoka S. Extramedullary plasmacytoma of the liver.
Nippon Ketsueki Gakkai Zasshi 1986;49:1412–7.
Demirhan B, Sökmensüer C, Karakayali H, Güngen Y, Doǧan
A, Haberal M. Primary extramedullary plasmacytoma of the
liver. J Clin Pathol 1997;50:74 – 6.
Nilüfer Güler, M.D.
Department of Medical Oncology
Hacettepe University Institute of Oncology
Ankara, Turkey
Author Reply
W
e read with interest the correspondence of Dr.
Güler concerning our article.1 In this article
we described the common therapies used for the
treatment of true extramedullary plasmacytomas
(EMPs). These tumors are sensitive to radiotherapy
and more often appear in the upper aerodigestive
tract. The response rate after radiotherapy is very
high, as indicated in the literature.2–3 Furthermore, our retrospective investigations have revealed that the combination of radiotherapy and
surgery provides the best survival rate, especially
for patients with an EMP in the upper aerodigestive area.1 EMPs that occur in regions outside of
the upper aerodigestive tract are treated mainly
by surgery. Chemotherapy has been given only
in rare cases, and the use of adjuvant chemotherapy has not affected the rate of conversion to myeloma.2 Soesan et al., who were mentioned in the
correspondence, achieved local control in 9 out of
18 patients treated with primary surgery and in 8
out of 12 patients treated with initial radiotherapy.
In 11 out of 19 patients they received local control
with chemotherapy. They observed 35 patients in
their study group.4 Because true EMP affects localized regions, surgical excision is very effective
and does not show the major negative side effects
242
CANCER January 1, 2000 / Volume 88 / Number 1
seen with chemotherapy. If complete removal of
an EMP is not possible, radiotherapy should also
be administered. Chemotherapy is the domain of
disseminated diseases, i.e., multiple myeloma.
However, in rare instances, if the EMP is very
large and adjacent vital organ structures preclude
radical intervention, preoperative chemotherapy
may be helpful in reducing the size of the plasmacytoma to enable organ preservation. Postoperative radiotherapy should be applied in all of these
cases.
REFERENCES
1.
2.
3.
4.
Alexiou C, Kau RJ, Dietzfelbinger H, Kremer M, Spieß JC,
Schratzenstaller B, et al. Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 1999;85:
2305–14.
Holland J, Trenkner DA, Wassermann TH, Fineberg B. Plasmacytoma: treatment results and conversion to myeloma.
Cancer 1992;69:1513–7.
Mayr N, Wen BC, Hussey DH, Burns P, Staples JJ, Doornbos JF, et al. The role of radiation therapy in the treatment
of solitary plasmacytomas. Radiother Oncol 1990;17:293–
303.
Soesan M, Paccagnella A, Chiarion-Sileni V, Salvagno L,
Fornasiero A, Sotti G, et al. Extramedullary plasmacytoma:
clinical behaviour and response to treatment. Ann Oncol
1992;3:51–7.
Christoph Alexiou, M.D.
Department of Otorhinolaryngology, Head and
Neck Surgery
Technical University of Munich
Munich, Germany
Wolfgang Arnold, M.D.
Head of the Department of Otorhinolaryngology,
Head and Neck Surgery
Technical University of Munich
Munich, Germany
Pathologic Findings from the
National Surgical Adjuvant
Breast Project (NSABP)
Eight-Year Update of
Protocol B-17
T
here are a number of issues raised in the article
by Fisher et al.1 relating directly to work that we
and our colleagues have published previously that
we would like to discuss. First, Fisher et al. refer to
two of our publications, one introducing the Van
Nuys Pathologic Classification2 and the other introducing the Van Nuys Prognostic Index (VNPI),3 and
state that “One group of investigators expanded
their classification within 1 year.”1 This suggests
that we published one classification, it was unsatisfactory, and we quickly amended it. This was not
the case. In 1995, we published the Van Nuys Pathologic Classification.2 This was a straightforward
histopathologic classification based on two well
defined biologic factors: nuclear grade and comedo-type necrosis. At the time of that publication,
it was clear to us that no histopathologic classification, regardless of which one was used or how
good it was, could ever, by itself, be adequate for
determining proper treatment. A small high grade
noninvasive lesion may be treated adequately by
excision alone if it has been removed completely.
However, a low grade lesion with margin involvement ultimately may progress to invasive disease
if part of it is left behind. A multivariate analysis
led us to believe that factors in addition to morphologic features, such as tumor size and margin
width (which reflect the anatomic distribution of
disease and the adequacy of surgical removal)
must be considered when planning treatment.
With this in mind, in 1996 we introduced the VNPI.3
The VNPI was not a histopathologic classification
and therefore not a modification of our previous
classification, and it clearly was not meant to replace it. Rather, the VNPI incorporated the Van
Nuys Pathologic Classification as one of its independent weighted features. The VNPI was devised
as a treatment planning aid to be used in conjunction with clinical experience, published data from
both prospective and retrospective studies, and
patient wishes. The VNPI relied on all of the key
factors (histopathologic classification, margin
width, and tumor size) that we and others had
shown to be important in predicting local recurrence after breast conservation for ductal carcinoma
in situ (DCIS).2– 6
Second, Fisher et al. attempted to test the Van
Nuys Pathologic Classification using data from the
National Surgical Adjuvant Breast Project (NSABP)
Protocol B-17 study. These data of Fisher et al. cannot be used to prove or disprove the worth of the
Van Nuys Pathologic Classification. The Van
Nuys Pathologic Classification distinguishes Groups
1 and 2 DCIS solely by the presence or absence of
any amount of comedo-type necrosis. Although
Fisher et al. used similar nuclear grading, they allowed as much as 33% of the ducts to contain comedo-type necrosis while considering the lesion equivalent to Van Nuys Group 1. They defined a lesion as
Correspondence
Group 2 only if comedo necrosis involved . 33% of
the ducts. Although we used the presence or absence of comedo necrosis to separate Groups 1 and
2, Fisher et al. allowed comedo necrosis to be
present in both their defined Groups 1 and 2,
thereby obfuscating the biologic differences between the two groups.
Finally, the accompanying editorial pointed out
that none of the existing classification schemes have
been proven prospectively and it welcomed the
NSABP’s updated results.7 This should not be misinterpreted by the reader to mean that the NSABP’s
pathology and classification are prospective. Although NSABP Protocol B-17 is a prospective randomized trial of two different treatments, their histopathologic data published in 19958 and in the
current update1 were not acquired prospectively.
The analysis of nine pathologic factors, including
grade, size, and margins, was retrospective and
based on central review of approximately 75% of the
patients. In contrast, although the Van Nuys patients were not randomized prospectively with regard to treatment, their histopathologic data were
collected prospectively and delineated from the onset.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
Fisher ER, Dignam J, Tan-Chiu E, Constantino J, Fisher
B, Paik S, et al. Pathologic findings from the National
Surgical Adjuvant Breast Project (NSABP) eight-year
update of Protocol B-17: intraductal carcinoma. Cancer
1999;86:429 –38.
Silverstein MJ, Poller DN, Waisman JR. Prognostic classification of breast ductal carcinoma in situ. Lancet 1995;345:
1154 –7.
Silverstein MJ, Lagios MD, Craig PH, Waisman JR, Lewinsky
BS, Colburn WJ, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer 1996;77:2267–74.
Lagios NM, Margolin FR, Westdahl PR, Rose NM. Mammographically detected duct carcinoma in situ. Frequency of
local recurrence following tylectomy and prognostic effect
of nuclear grade on local recurrence. Cancer 1989;63:619 –
24.
Silverstein MJ, Lagios MD, Groshen S, Waisman JR,
Lewinsky BS, Martino S, et al. The influence of margin
width on local control in patients with ductal carcinoma
in situ (DCIS) of the breast. N Engl J Med 1999;340:1455–
61.
Boyages J, Delaney G, Taylor R. Predictors of local recurrence after treatment of ductal carcinoma in situ: a metaanalysis. Cancer 1999;85:616 –28.
Morrow M. Understanding ductal carcinoma in situ: a step
in the right direction. Cancer 1999;86:375–7.
Fisher ER, Constantino J, Fisher B, Palekar AS, Redmond C,
Mamounas E. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17: intra-
243
ductal carcinoma (ductal carcinoma in situ). Cancer 1995;
75:1310 –9.
Melvin J. Silverstein, M.D.
Norris Comprehensive Cancer Center
Keck School of Medicine
University of Southern California
Los Angeles, California
Michael D. Lagios, M.D.
Breast Cancer Consultation Service
St. Mary’s Hospital
San Francisco, California
Author Reply
W
e do not wish to engage in an historic or semantic debate with Drs. Silverstein and Lagios
regarding the genesis of the Van Nuys Prognostic
Index. However, I cannot find the use of the word
“unsatisfactory” anywhere in our publication1
concerning the Van Nuys Pathologic Classification.
Indeed we utilized the word “expanded,” which
they also indicate in their letter. Actually, one of
the definitions of unsatisfactory is inadequate.2 As
I understand their comments, the pathologic classification was indeed inadequate and therefore was
expanded. Drs. Silverstein and Lagios indicate in
their letter and I quote “The VNPI was not a histopathologic classification and therefore not a
modification of our previous classification, and it
clearly was not meant to replace it.” It is not indicated in our publication that this was the intent of
the VNPI. Yet, one might argue that the VNPI really
is a pathologic classification because estimation of
tumor size often is histopathologic, as is assessment
of the extent of excision. Drs. Silverstein and Lagios
also state that the “The VNPI was devised as a treatment planning aid to be used in conjunction with
clinical experience, published data from both prospective and retrospective studies, and patient
wishes.” First, I know of no truly prospective studies
performed by the Van Nuys group. Second, I am
somewhat bemused as to where “patient wishes”
enter into the development of a protocol for a scientific prospective study or classification of diseases. Indeed, this confession further substantiates
our belief as to the actual value of the VNPI (vide
infra).
I believe Drs. Silverstein and Lagios are overreacting to our observation that we could not find an
244
CANCER January, 1 2000 / Volume 88 / Number 1
absolute fit with the Van Nuys Pathologic Classification with our material. They are correct that our
use of an absent/slight group of comedo necrosis
differs from their recognition of comedo necrosis as
simply being absent or present. Our “cutoff” points
for comedo necrosis were based on our perception
that the significance of comedo necrosis might be
quantitative. We have been reluctant to regard the
presence of a few ducts containing comedo necrosis
as having similar significance to instances in which
this process might be far more extensive. Our view is
supported by our findings of low and high risk
groups for ipsilateral breast tumor recurrence based
on the degree of comedo necrosis according to the
groups in our algorithm. Actually, I expected such a
query and our ongoing pathologic review of ductal
carcinoma in situ in the National Surgical Adjuvant
Breast Project Protocol B-24 does include an “absent comedo necrosis” category, which might help
resolve this issue.
I believe the final comments of Drs. Silverstein and Lagios are quite revealing. They, as well as
those noted above relating to prospective studies,
indicate a certain lack of understanding of prospective clinical trials and their significance. Protocol
B-17 was “a treatment protocol” and randomization
was not based on any pathologic characteristics.
These latter obviously were “retrospectively” ob-
tained. This type of retrospective examination is not
to be devalued because it certainly allows for the
bona fide recognition of subsets of patients in various treatment groups. Conversely, Drs. Silverstein
and Lagios “boast” that their pathologic findings
were collected “prospectively and delineated from
the onset.” However, and most important, treatment was not randomized on the basis of such
findings but unfortunately was based on bias provoked by the pathologic characterization of the tumors—a most injudicious practice for evaluating
treatment.
REFERENCES
1.
2.
Fisher ER, Dignam J, Tan-Chiu, Constantino J, Fisher
B, Paik S, et al. Pathologic findings from the National
Surgical Adjuvant Breast Project (NSABP) eight-year
update of Protocol B-17: intraductal carcinoma. Cancer
1999;86:429 –38.
The American Heritage dictionary of the English language.
3rd edition. Boston: Houghton Mifflin Co., 1992.
Edwin R. Fisher, M.D.
Headquarters Pathology
National Surgical Adjuvant
Breast and Bowel Project (NSABP)
Allegheny General Hospital
Continuing Care Center
Pittsburgh, Pennsylvania
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