ANATOMIC PATHOLOGY
Original Article
Comparison of DNA Content, S-Phase
Fraction, and Survival Between Medullary
and Ductal Carcinoma of the Breast
DEBORAH L. COOK, MD, AND DONALD L. WEAVER, MD
the two groups. Thirteen of 20 patients (65%) with MC (average followup 130 months) were alive at the end of the study period compared to
12 of 20 patients (60%) with IDC (average follow-up 160 months). The
difference in crude survival was not statistically significant (P = .867).
However, there was a tendency toward early death in MC and late death
in IDC. Within the TNM stage-matched patients, no significant difference was demonstrated for tumor size or nodal status when these variables were examined separately.
In conclusion, statistically significant differences in DNA content and
proliferative fraction exist between medullary carcinoma of the breast
and ductal carcinoma. The biologic and clinical differences demonstrated in this analysis warrant careful consideration before including
cases of medullary carcinoma in studies evaluating newer prognostic
variables in breast cancer. (Key words: Breast neoplasms; Flow cytometry; DNA; Medullary carcinoma; S-phase fraction) Am J Clin Pathol
1995;104:17-22.
Medullary carcinoma (MC) of the breast has been regarded as a subtype of breast carcinoma with a relatively favorable prognosis despite
its high nuclear grade and high mitotic index. High nuclear grade and
high mitotic index have been correlated with DNA aneuploidy and high
S-phase fraction (SPF) byflowcytometry. Generally in breast cancer,
these histologic and DNA content features predict a less favorable
prognosis. To address this paradox, all cases of MC of the breast (20
of 1,365 carcinomas (1.5%]) diagnosed between 1968 and 1982 were
compared to age- and stage-matched cases of infiltrating ductal carcinoma (IDC) diagnosed during the same time period. All of the MC and
80% of the IDC had one or more DNA aneuploid stem lines. Average
total SPF was 8.1% for MC and 4.8% for IDC. DNA analysis was performed from paraffin blocks (average CV: 4.5% DNA diploid; 4.1%
DNA aneuploid), and subjected to computer modeled analysis. Statistically significant differences between presence or absence of DNA aneuploidy (P = .035) and total SPF (P = .029) were demonstrated between
Medullary carcinoma of the breast is a relatively rare subtype
of breast carcinoma, which was first recognized by Moore and
Foote1 as a distinct entity in 1949, although allusions to this
tumor can be found in the literature predating their account. 2
Many analyses of medullary carcinoma, like that of Moore and
Foote, indicate a more favorable outcome when compared with
other subtypes of invasive breast carcinoma.3"5 However, a majority of the early investigations suffered from lack of a uniform
histopathologic definition of medullary carcinoma, and of appropriate control groups for prognostic comparison. In 1977,
Ridolfi and colleagues defined precise morphologic criteria for
the diagnosis of medullary carcinoma and applied their criteria
to a series of patients with tumors previously diagnosed as, or
with features of, medullary carcinoma. 6 Those patients with tumors possessing the diagnostic criteria for medullary carci-
noma showed an improved survival at 10 years when compared
to non-medullary infiltrating ductal carcinoma (84% versus
63%, respectively). Subsequent application of these strict criteria for the definition of typical medullary carcinoma have
confirmed the favorable prognosis of medullary carcinoma. 7,8
The unusual combination of histologic features, including a
syncytial architecture with absence of glandular pattern, well
circumscribed margin, and lymphocytic stromal infiltrate,
characterize medullary carcinoma. Additionally, medullary
carcinoma exhibits marked nuclear pleomorphism and increased mitotic activity with a tendency to be larger than typical infiltrating ductal carcinoma at initial presentation. However, these histologic features traditionally predict a poor
prognosis, as previously noted, patients with medullary carcinoma generally have longer disease-free and overall survival
than those with ductal carcinoma. The reason for this paradox
is not clear.
Flow cytometric analysis of DNA content (ploidy) and cell
From the Department of Pathology, the University of Vermont College ofMedicine, the Medical Center Hospital of Vermont, and the Ver- cycle proliferative activity (S-phase fraction) has been applied
mont Cancer Center, Burlington, Vermont.
as a prognostic variable in several common tumors 9 1 0 including breast carcinoma." 1 2 The development of nuclear extracPresented in part at the Spring Meeting of the American Society of
tion techniques from paraffin-embedded tissue has allowed retClinical Pathologists, March 27-April 1, 1993, Chicago, Illinois.
rospective DNA analysis of archival tissue from patients with
Manuscript received October 3, 1994; revision accepted March 3,
known clinical outcome. 1314 Tumors that have highly anaplas1995.
tic nuclei and numerous mitotic figures typically are DNA anAddress reprint requests to Dr. Weaver: Department of Pathology,
euploid and have a high S-phase fraction.15"'7 Furthermore,
University of Vermont College of Medicine, Burlington, VT 05405current evidence suggests that patients with DNA aneuploid or
0068.
17
18
ANATOMIC PATHOLOGY
Original Article
high S-phase fraction breast tumors have a greater likelihood of
recurrence and shorter overall survival.16'8'9
To address the apparent contradiction of prognostic features
and clinical outcome in medullary carcinoma, we evaluated the
relationship between DNA content, S-phase fraction, and survival in age- and stage-matched cases of medullary and infiltrating ductal carcinoma of the breast.
MATERIALS AND METHODS
All cases of medullary carcinoma of the breast diagnosed before 1983 at the Medical Center Hospital of Vermont were
identified from the files of the Vermont Cancer Center Tumor
Registry. Histologic sections, pathology reports, and tumor registry clinical files were reviewed for each case. The neoplasms
were re-classified according to the histologic criteria set forth
by Ridolfi and colleagues6 for medullary carcinoma, and were
staged by the American Joint Committee TNM system.20 Criteria for inclusion in the study were verification of the diagnosis
of medullary carcinoma and availability of sufficient paraffinembedded tissue for flow cytometric analysis. Age- and stagematched case controls of infiltrating ductal carcinoma were selected from the files of the Vermont Cancer Center Tumor
Registry. A control patient with infiltrating ductal carcinoma
diagnosed in the same year, with the same stage and an age
within 5 years (±), was selected from the registry at random for
each study patient with medullary carcinoma.
The samples for DNA flow cytometry were deparaffinized
and dissociated according to a modification of the method described by Hedley.14 For each case, one or two (depending on
relative cellularity of the tissue block) 50 /x sections were obtained from an average of 2 (range 1-4) representative paraffinembedded tissue blocks, and analyzed separately. Tissue sections were deparaffinized using xylene, then rehydrated sequentially in a series of graded ethanol solutions (100%, 95%,
70%, 50%). The rehydrated tissue was held in distilled water
overnight at room temperature. The following morning,
nuclear suspensions were prepared by incubation with 0.5%
pepsin (Sigma, St. Louis, MO) at 37 °C for 30 minutes combined with periodic vigorous vortexing. After washing with citrate buffer, the nuclei were stained in a solution of 0.05 mg/
mL propidium iodide (Sigma), 2% Triton X-100 (v/v) in citrate
buffer and incubated at 37 °C for 30 minutes. The stained
nuclear suspensions werefilteredthrough 100 pM nylon mesh
(Small Parts, Miami, FL) to remove excess tissue then treated
with ribonuclease A (180 U/mL, final concentration) (Worthington, Freehold, NJ) at 37 °C for 30 minutes. Suspensions
were allowed to equilibrate at 4 °C for a minimum of 1 hour
before analysis. Flow cytometric analysis was performed on an
EPICS Profile flow cytometer (Coulter, Hialeah, FL). Events
above channel 10, as detected by the propidium iodide photomultiplier channel, were collected. DNA histograms were analyzed using Verity:ModFit cell cycle analysis software, version
5.01 (Verity Software House, Topsham, ME). Single-cut debris
subtraction algorithms were employed. Software aggregate correction was enabled and no prior hardware or software gating to
eliminate doublets was used. DNA histograms with two distinct
peaks and a valley between the peaks at least 25% the height of
the shorter peak were interpreted as DNA aneuploid. A single
trapezoid was used to model S-phase. S-phase was calculated
for the aneuploid cell population only (aneuploid SPF), and as
a function of the total cell population (total SPF). S-phase was
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
DNA Content (Channel Number)
FIG. 1. DNA histogram demonstrating DNA aneuploidy in medullary
carcinoma (case 18, Table 1).
not calculated for DNA diploid populations when the bases of
the DNA diploid and DNA aneuploid peaks overlapped. If two
DNA histograms from a single patient were acceptable for analysis, the histogram with the least debris and best CV was selected and used for statistical analysis (Fig. 1).
Pearson chi-square analysis was used for correlation of survival status (alive, dead, dead of disease), ploidy (DNA diploid,
DNA aneuploid, DNA multiploid), tumor size, and nodal status, overall stage and tumor type (MC, IDC). These variables
were independently correlated with stage, tumor type and survival status (alive, dead, dead of disease; and after excluding
death from other causes). Two-tailed t-test was used to analyze
differences in flow cytometric DNA characteristics (DNA index, percent DNA aneuploid, total SPF, total aneuploid SPF)
by tumor type (MC, IDC). Analysis of variance was used to
determine whether differences in theseflowcytometric characteristics are prognostic for stage of disease or survival status.
Patient survival by tumor type was evaluated by the method of
Mantel-Cox.
RESULTS
Review of 28 surgical cases diagnosed as medullary carcinoma between the years of 1968 and 1982 resulted in 20 cases
(20 of 1,365 total cases of breast carcinoma [1.5%]) that satisfied the criteria for inclusion in the study (Figs. 2 and 3). The
mean age of patients with medullary carcinoma at the time of
diagnosis was 51 years (range 28-77 years) compared to 52
years (range 28-79 years) for patients with infiltrating ductal
carcinoma. The cases included TNM stages I, II, and III. In no
case were there distant metastases at the time of diagnosis (stage
IV). Within the TNM-stage matched patient groups, no significant difference was demonstrated for tumor size (0.392) or
nodal status (P = .723) when these variables were examined
separately, indicating an absence of selection bias. Of the infiltrating ductal carcinomas, nine (45%) were well differentiated,
seven (35%) were moderately differentiated, and four (20%)
were poorly differentiated. All patients were treated initially
with surgery. Eight patients with medullary carcinoma and
seven patients with infiltrating ductal carcinoma received adjuvant therapy (radiation, chemotherapy, hormonal, or combination) in addition to surgery. Clinical follow-up for patients
A.J.C.P.-July 1995
COOK AND WEAVER
19
DNA Content in Medullary Carcinoma
01
c
i!
0.8
•5 C
0.7 ••
II
3
t
0.6
• Medullary
°a
' Ductal
o
0.3
-t-
0
25
-t-
50
-t-
-+-
-4-
75 100 125 150 175 200 225 250 275
Months
FlG. 2. Medullary carcinoma with characteristic circumscribed margin,
syncytial growth pattern, and lymphocytic stromal infiltrate (hematoxylin and eosin, X60).
with medullary carcinoma averaged 129.9 months, whereas the
average was 159.9 months for those with infiltrating ductal carcinoma (P= .164).
Of the 20 study patients with medullary carcinoma, 13 (65%)
were alive, 4 (20%) were dead of disease, and 3 (15%) were dead
of other causes at the end of the study period. Of the 20 study
patients with infiltrating ductal carcinoma, 12 (60%) were alive,
3 (15%) were dead of disease, and 5 (25%) died of other causes.
There was no statistically significant difference in overall survival between the two groups (P = .867). In addition, no difference in survival was demonstrated when deaths from other
causes were excluded (P = .737). The patients with medullary
carcinoma had a greater tendency to recur early (4-15 months,
average 10 months) and die of their disease (6-83 months, average 36 months) than the infiltrating ductal carcinomas (time
to recurrence, 58-142 months, average 91 months; time to
death, 89-217 months, average 155 months). However, the
probability of long-term survival was higher in medullary carcinoma (Fig. 4). Survival status of both patient groups was sig-
FIG. 4. Probability of survival for patients with medullary carcinoma or
infiltrating ductal carcinoma of the breast. No significant difference was
demonstrated (P = .867). However, medullary carcinoma tended to
recur earlier and have a higher probability of long-term survival.
nificantly correlated with clinical stage of disease (P = .009) as
well as tumor size (P = .020). However, no significant difference in survival was identified for nodal status (P = . 5 81).
All of the cases of medullary carcinoma and 80% of the cases
of infiltrating ductal carcinoma had one or more DNA aneuploid stem lines (P = .035) (Table 1). The mean coefficient of
variation (CV) was 4.5% for DNA diploid peaks (range 1.9-9.7)
and 4.1% for DNA aneuploid peaks (range 2.0-10.2). Average
total S-phase fraction was 8.1% for medullary carcinoma (range
1%—20%) and 4.8% for infiltrating ductal carcinoma (range
1 %-19%). Statistically significant differences were observed between the two groups for total S-phase fraction (P = .029), total
DNA aneuploid S-phase fraction (P = .002), and percent DNA
diploid (P = .046).
When flow cytometrically determined prognostic factors
(DNA index, percent DNA aneuploid, total S-phase fraction,
total DNA aneuploid S-phase fraction) were evaluated as independent predictors of survival, no statistical significance was
demonstrated (at the 0.050 level). Furthermore, no statistically
significant correlation was observed between these factors and
clinical stage (at the 0.050 level) or DNA content (ploidy) and
clinical stage (P = .774).
DISCUSSION
FlG. 3. Medullary carcinoma with high grade nuclei and abundant mitoticfigures(hematoxylin and eosin, X250).
Medullary carcinoma, a relatively rare subtype of mammary
carcinoma, is usually considered to have a better prognosis
when compared to the common forms of infiltrating breast carcinoma. However, use of conventional histopathologic prognostic parameters, such as nuclear grade and mitotic rate,
would indicate the opposite to be true; namely, that medullary
carcinoma is a rapidly proliferating, high grade neoplasm. This
study was designed to investigate the correlation between DNA
content, S-phase fraction, and survival for medullary carcinoma compared to that for infiltrating ductal carcinoma of the
breast using flow cytometric techniques.
Based on our results, we have observed that medullary carcinoma of the breast is more likely to be DNA aneuploid than
age- and stage-matched cases of infiltrating ductal carcinoma.
Furthermore, a larger percentage of the DNA aneuploid cases
Vol. 104-No. I
20
ANATOMIC PATHOLOGY
Original Article
TABLE 1. SUMMARY OF CLINICAL, PATHOLOGIC, AND FLOW CYTOMETRIC DATA
Case
Dx
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Med
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Duct
Status/months
AW 190
AW 193
AW 234
AW 175
AW219
AW 118
AW 126
AW 166
AW 116
AW 107
AW 85
AW 247
AW 55
DID 195
DID 145
DID 83
DOD 6
DOD 23
DOD 83
DOD 32
AW 197
AW 126
AW 229
AW 179
AW 254
AW 230
AW 110
AW 156
AW 118
AW 128
AW 187
AW 263
DID 207
DID 117
DID 112
DID 56
DID 65
DOD 89
DOD 158
DOD217
Ploidy (Dl)
CV
T-SPF
An-SPF
Stage
M(1.2, 1 •8)
A (1.1)
A (1.2)
A (1.1)
A (1.7)
A (2.0)
M ( l . l , 1 •3)
A (1.9)
A (1.2)
M (0.9, 1•6)
A (1.5)
A (1.4)
A (1.5)
A (1.3)
A (1.1)
A (2.4)
A (1.7)
A (1.7)
M(l.1,2.0)
M(1.2, 1 •8)
A (2.9)
D(1.0)
A (1.5)
A (1.7)
A (1.2)
A (1.3)
A (1.6)
A (1.7)
A (1.8)
A (1.8)
A (1.6)
M(1.4, 1 .6)
A (1.9)
A (1.2)
A (1.4)
D(1.0)
M(1.5, • 8)
D(1.0)
A (1.3)
D(1.0)
7.0
3.2
3.1
3.8
2.0
3.9
3.2
6.9
3.6
3.3
2.3
3.6
1.9
6.9
9.7
7.9
5.5
4.6
1.9
5.7
4.5
4.4
3.9
3.4
3.6
6.7
4.5
4.6
3.4
5.0
6.1
6.9
6.6
4.2
3.9
2.9
6.9
5.0
6.4
4.6
1.2
9.1
8.1
12.5
7.8
12.7
13.2
10.0
9.7
5.6
15.5
8.1
4.1
7.9
7.1
3.9
1.3
3.9
8.0
7.2
4.7
2.7
11.4
3.3
1.9
2.1
5.8
3.3
7.0
3.9
2.9
19.4
1.8
1.4
5.1
2.5
4.5
3.3
6.0
3.4
1.5
10.7
10.4
23.2
17.3
33.0
20.9
20.0
15.8
9.9
19.7
15.7
4.6
12.8
16.7
6.5
15.8
6.5
9.8
19.1
13.9
0.0
23.5
6.6
7.4
0.2
8.8
3.7
6.0
6.1
15.6
12.1
3.7
2.2
5.9
0.0
6.6
0.0
7.0
0.0
II (T3N0)
II(TINI)
II (T2N0)
II (T2N0)
II (T2N0)
I(TINO)
II (T2N0)
IKT2N1)
I (UNO)
I(T1N0)
I(TINO)
II(TINI)
II (T2N0)
IIKT3N1)
II (T2N0)
II (T3N0)
II (T2N0)
III(T3N1)
I(TINO)
II (T2N0)
II(TINI)
I(TINO)
II (T2N0)
II (T2N0)
II(T2N1)
II (T2N0)
II (T2N0)
I(TINO)
II (T2N0)
I(TINO)
II(T2N1)
I(TINO)
I(T1N0)
III(T3N1)
II (T2N0)
II (T2N0)
III(T4N1)
II (T2N0)
II (T2N0)
II(TINI)
Med = medullary carcinoma; Duct = ductal carcinoma; AW = alive without disease; DID = dead of intercurrent disease; DOD = dead
of disease; M = multiploid; A = aneuploid; D = diploid; Dl = DNA index; CV = coefficient of variation; T-SPF = total S-phase; An-SPF =
total aneuploid S-phase.
of medullary carcinoma showed multiple DNA aneuploid populations (DNA multiploid) as compared to the DNA aneuploid
cases of infiltrating ductal carcinoma. Total S-phase fraction,
calculated for all populations (DNA diploid and DNA aneuploid), was higher for the medullary carcinoma cases as was
the S-phase fraction calculated for DNA aneuploid populations
alone with exclusion of the DNA diploid populations (DNA
aneuploid S-phase). Thesefindingsare commensurate with the
definitional features of medullary carcinoma that include high
nuclear and histologic grades, lack of glandular differentiation,
as well as the presence of numerous mitoticfiguresand an apparent rapid growth rate.
Generally, tumors with DNA aneuploid, DNA tetraploid,
and mosaic DNA distribution demonstrate morphologic parameters of poor differentiation and higher tumor grades. The
S-phase fraction as a determination of the percentage of cells
synthesizing DNA is considered to be a reflection of the prolif-
erative capacity and behavior of a tumor. Although correlation
between DNA content and/or S-phase fraction and histologic
tumor grade has been demonstrated in studies of breast carcinoma, few have included lower frequency histologic subtypes
such as medullary carcinoma. In one report, 85% of cases of
typical medullary carcinoma (39 cases) were found to be DNA
aneuploid.21 Others, such as our study, have found a significantly higher S-phase fraction for medullary carcinoma when
compared to other histologic subtypes.22"24
Neither the presence of DNA aneuploidy nor the S-phase
fraction was able to independently predict survival for patients
with either medullary or infiltrating ductal carcinoma. Accordingly, there was no correlation between DNA content or cell
cycle activity and clinical stage of disease defined as a function
of tumor size, nodal status, and presence of metastases. The
precise role of DNA quantification and cell cycle analysis as
prognostic indicators in breast carcinoma has not been deter-
A.J.C.P.'July 1995
21
COOK AND WEAVER
DNA Content in Medullary Carcinoma
mined. Although no clear correlation between DNA aneuploidy, S-phase fraction and stage has been established, DNA
aneuploid tumors generally are associated with shorter diseasefree and overall survival. 1216 ' 8 This was not corroborated by
our study for either patient population. However, the study
population was small because of the case-control study design.
No significant difference in overall survival was observed between the patients with medullary carcinoma and those with
infiltrating ductal carcinoma during the study period. Traditionally, medullary carcinoma has been considered to have a
more favorable outcome when compared to other types of malignant breast tumors. 1,3A6 However, several analyses indicate
that medullary carcinoma has no better survival than other
more common forms of breast carcinoma. 25-28 The lack of consensus regarding the prognosis of medullary carcinoma is because of the variability of tumor classification using histopathologic criteria,8'29 as well as the influence of control group
selection and study size. We employed the strict criteria of Ridolfi and colleagues6 for inclusion of cases as medullary carcinoma ("typical"), and selected age- and stage-matched control
cases of infiltrating ductal carcinoma diagnosed in the same
period. Medullary carcinoma represented only 1.5% of the
breast carcinomas diagnosed during the study period at the
Medical Center Hospital of Vermont, an observed frequency
comparable to that reported by others. 30 The relatively small
study population limited the ability to detect differences in survival.
A distinct pattern of survival emerged from the clinical follow-up data in this study. Patients with medullary carcinoma
tended to have earlier recurrences (average of 10 months from
diagnosis), and subsequently die of their disease (average of 36
months from diagnosis), than patients with infiltrating ductal
carcinoma (average of 91 months to recurrence, average of 155
months to death). However, the probability of long-term survival was higher for patients with medullary carcinoma. In
other words, a patient who survives 3 to 5 years after a diagnosis
of medullary carcinoma has a high probability of long-term
survival. Although this trend was not statistically significant in
this study, a similar trend has been noted previously by other
authors 31 , including Ridolfi and colleagues6 who observed that
the majority of patients who died of medullary carcinoma did
so within 5 years of initial treatment. This was in contrast to
the continued decline in survival during the entire study period
for the group of patients with infiltrating ductal carcinoma. In
addition, the trend toward early death, but better overall longterm survival in medullary carcinoma with a crossover point at
18 years, complicated the statistical ability to detect survival
differences between medullary carcinoma and ductal carcinoma of the breast.
In summary, medullary carcinoma of the breast is more
likely to be DNA aneuploid and have a higher S-phase fraction
than age- and stage-matched control cases of infiltrating ductal
carcinoma. These findings are consistent with the cytologic features that characterize medullary carcinoma. Although a statistically significant survival advantage for medullary carcinoma
was not demonstrated, there was a trend toward early relapse
and death in a subset of patients with medullary carcinoma and
a trend toward long-term survival in the remainder of patients
with medullary carcinoma. The underlying genomic causes for
these biologic and clinical differences between medullary carcinoma and typical ductal carcinoma of the breast are not currently known and appear to be independent of DNA content
and proliferative activity. Other variables need to be explored
to explain the paradox between histologic appearance and clinical behavior in medullary carcinoma of the breast.
Acknowledgments. The authors thank Janet Schwarz for expert technical assistance in obtaining DNA histograms, Martha Judd for case
identification, Pamela Vacek for statistical analysis, and Judith Kessler
for preparation of photomicrographs and figures.
REFERENCES
1. Moore OS, Foote FW. The relatively favorable prognosis of medullary carcinoma of the breast. Cancer 1949;2:635-642.
2. Geschickter CF. Disease of the Breast: Diagnosis, Pathology,
Treatment, ed. 2. Philadelphia: Lippincott, 1945, pp 565-568.
3. Richardson WW. Medullary carcinoma of the breast: A Distinctive tumour type with a relatively good prognosis following radical mastectomy. Br J Cancer 1956; 10:415-426.
4. Bloom HG, Richardson WW, Field JR. Host resistance and survival in carcinoma of the breast: A study of 104 cases of medullary carcinoma in a series of 1,411 cases of breast cancer for 20
years. Br Med J 1970;3:181-188.
5. Maier WP, Rosemond GP, Goldman LI, Kaplan GF, Tyson RR.
A 10- year study of medullary carcinoma of the breast. Surg
Gynecol Obslel 1977; 144:695-698.
6. Ridolfi RL, Rosen PP, Port A, Kinne D, Mike V. Medullary carcinoma of the breast: A clinicopathologic study with 10-year follow-up. Cancer 1977;40:1365-1385.
7. Rapin V, Contesso G, Mouriesse H, et al. Medullary breast carcinoma: A reevaluation of 95 cases of breast cancer with inflammatory stroma. Cancer 1988;61:2503-2510.
8. Wargotz ES, Silverberg SG. Medullary carcinoma of the breast:
A clinicopathologic study with appraisal of current diagnostic
criteria. Hum Pathol 1988; 19:1340-1346.
9. Coon JS, Landay AL, Weinstein RS. Biology of disease: Advances
inflowcytometry for diagnostic pathology. Lab Invest 1987; 57:
453-479.
10. Koss LG, Czerniak B, Herz F, Wersto RP. Flow cytometric measurements of DNA and other cell components in human tumors: A critical appraisal. Hum Pathol 1989;20:528-548.
11. Sigurdsson H, Baldetorp B, Borg A, et al. Indicators of prognosis
in node-negative breast cancer. N Engl J Med 1990;322:10451053.
12. Clark GM, Dressier LG, Owens MA, et al. Prediction of relapse or
survival in patients with node-negative breast cancer by DNA
flow cytometry. N Engl J Med 1989;320:627-633.
13. Hedley DW, Friedlander ML, Taylor IW, et al. Method for analysis of cellular DNA content of paraffin-embedded pathological
material usingflowcytometry. JHislochem Cvtochem 1983; 31:
1333-1335.
14. Hedley DW. Flow cytometry using paraffin-embedded tissue: Five
years on. Cytometry 1989; 10:229-241.
15. Feichter GE, Mueller A, Kaufmann M, et al. Correlation of DNA
flow cytometric results and other prognostic factors in primary
breast cancer. Int J Cancer 1988;41:823-828.
16. Hedley DW, Rugg CA, Gelber RD. Association of DNA index and
S-phase fraction with prognosis of nodes positive early breast
cancer. Cancer Res 1987;47:4729-4735.
17. McDivitt RW, Stone KR, Craig RB, et al. A proposed classification
of breast cancer based on kinetic information: Derived from a
comparison of risk factors in 168 primary operable breast cancers. Cancer 1986;57:269-276.
18. Kallioniemi O, Blanco G, Alavaikko M, et al. Improving the prognostic value of DNA flow cytometry in breast cancer by combining DNA index and S-phase fraction: A proposed classification of DNA histograms in breast cancer. Cancer 1988,62:
2183-2190.
Vol. 104.No. I
22
ANATOMIC PATHOLOGY
Original Article
19. Visscher DW, Zarbo RJ, Greenawald KA, Crissman JD. Prognostic significance of morphological parameters andflowcytometric DNA analysis in carcinoma of the breast. Pathol Annual
1990:24:171-210.
20. American Joint Committee on Cancer. Manual for Staging of Cancer, ed 3. Philadelphia: J.B. Lippincott, 1988, pp 145-150.
21. Fisher ER. Kenny JP, Sass R, et al. Medullary carcinoma of the
breast revisited. Breast Cancer Res Treat 1990; 16:215-229.
22. Olszewski W, Darzynkiewicz Z, Rosen PP, Schwartz MK, Melamed MR. Row cytometry of breast carcinoma: II. Relation of
tumor cell cycle distribution to histology and estrogen receptor.
Cancer 1981;48:985-988.
23. Moran RE, Black MM, Alpert L, Straus MJ. Correlation of cellcycle kinetics, hormone receptors, histopathology, and nodal
status in human breast cancer. Cancer 1984;54:1586-1590.
24. Meyer JS. McDivitt RW, Stone KR, Prey MU, Bauer WC. Practical breast carcinoma cell kinetics: review and update. Breast
Cancer Res Treat 1984;4:79-88.
25. Schwartz GF. Solid circumscribed carcinoma of the breast. Ann
Surg 1969:169:165-173.
26. Flores L, Arlen M, Elguezabal A, Livingston SF, Levowitz BS.
Host tumor relationships in medullary carcinoma of the breast.
Surg Gynecol Obstet 1974; 139:683-688.
27. Ellis IO, Galea M, Broughton N, et al. Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology
1992;20:479-489.
28. Black CL, Morris DM, Goldman LI, McDonald JC. The significance of lymph node involvement in patients with medullary
carcinoma of the breast. Surg Gynecol Obstet 1983; 157:497499.
29. Pedersen L, Zedeler K, Hoick S, Schiodt T, Mouridsen HT. Medullary carcinoma of the breast, proposal for a new simplified
histopathologic definition. Br J Cancer 1991;63:591-595.
30. Pedersen L, Hoick S, Schiodt T. Medullary carcinoma of the
breast. Cancer Treatment Rev 1988; 15:53-63.
31. McDivitt RW, Stewart FW, Berg JW. Tumors of the Breast. Atlas
of Tumor Pathology. Second Series, Fascicle 2. Washington,
DC: Armed Forces Institute of Pathology, 1968, pp 57-62.
AJ.C.P.-July 1995