154

The Prognosis of Breast Cancer in Males

A Report of 335 Cases
Vincenf F. Guiizee, M.D., M.P.H.,' Hakan Olsson, M.D., Ph.D.,t Torgil Moller, M.D., Plz.D.,t Rick C. Shallenberger, M.P.H.,* I. W . van den Blink, M.D.,S Zoltarz Peter, M.D.,fj Michel Durarzd, M.D.,II Stanley Dische, M.D.,V Franz 1. Cleton, M.D.,# Roelof Zewuster,** Mei Fang Cui,tt Warren Lane, Ph.D.,$$ and Rudolf Richter, M.D.55

Background. Because of the relative rarity of breast cancer in males, data have not been sufficient to support a definitive analysis of pertinent prognostic factors. Remarkably, no studies of male patients with breast cancer have presented survival information based on the number of histologically positive axillary nodes, the most sensitive single indicator of prognosis in women with breast cancer. Methods. In this study, the clinical course of breast cancer was documented for 335 male patients registered from 1965 through 1986. For patients to be eligible, diagnoses had to be made within 3 months of registration and the patients had to have histologic confirmation and receive part or all of their initial treatment at 1 of 1 1cancer centers participatingin the International Patient Data Exchange System. Results. The survival rate at 10 years was 84% for patients with histologically negative nodes, 44% for those with one to three positive nodes, and 14% for the group

with four or more histologically positive nodes. The survival rates at 5 years were go%, 73'/0, and 55%, respectively. In a multivariable analysis, the risk of death due to breast cancer for a patient with four or more histologically positive nodes was 6.75 times that of a patient with negative nodes. Conclusions. The findings of the authors indicate the following: (1)The number of histologically positive axillary nodes and, to a lesser degree, tumor diameter are significant prognostic factors for breast cancer in male patients. (2) The prognosis of breast cancer is the same in male and female patients when compared on the basis of the number of histologically positive nodes. Cancer 1993; 71 :154-61. Key words: breast cancer male, prognosis, survival, axillary nodes, multivariable analysis.

From the *Department of Patient Studies, University of Texas M. D. Anderson Cancer Center, Houston, Texas; tLund University Hospital, Lund, Sweden; $Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; 5National Institute of Oncology, Budapest, Hungary; ((FoundationBergonie, Bordeaux, France; TRegional Center for Radiotherapy and Oncology, Mt. Vernon Hospital, Northwood, Middlesex, England; #University Hospital, Leiden, The Netherlands; **Netherlands Cancer Institute, Amsterdam, The Netherlands; ItCancer Institute, Chinese Academy of Sciences, Beijing, China; $$Roswell Park Cancer Institute, Buffalo, New York; and Westdeutsches Tumorzentrum, Essen, Germany. The authors thank Harold Andersson, Ph.D., Joe Ensor, Ph.D., and Kenneth Hess, Ph.D., for their statistical contributions during this study. The International Cancer Patient Data Exchange System is a project of the Committee on International Collaborative Activities of the International Union Against Cancer. Address for reprints: Vincent F. Guinee, M.D., M.P.H., Department of Patient Studies, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 214, Houston, TX 77030. Accepted for publication May 27, 1992.

Because of the relative rarity of breast cancer in males, the literature has been dominated by reviews, collected case reports, and original series with small numbers of cases. Data available to these authors were not sufficient to support a definitive analysis of the prognosis of male patients with breast cancer. By the early 1970s, a number of observers believed that survival of male and female patients with breast cancer was ~omparable.'-~ However, 10 years later6 and 20 years later7 investigators still reported that their data showed a poorer prognosis for male patients. At best, current texts and reviewss-" state that, although male and female patients with negative axillary nodes may have equivalent survival rates, male patients with histologically positive axillary nodes have a worse prognosis than women with positive nodes. In contrast to the detailed pathologic data available on female patients with breast cancer, prognostic evaluation of men with breast cancer usually has been based on clinical data.3,"-'4 Only a few case series have re-

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ported the histologic status of axillary node^.^,'^-'^ Remarkably, no studies of men with breast cancer have presented survival information based on the number of histologically positive axillary nodes. And yet, the number of histologically involved axillary nodes is considered to be the most sensitive single indicator of prognosis in women. 21 This correlation was reported by Fisher et a1.22 in 1968 and confirmed in subsequent studies,2324 As long as information on the survival of men with breast cancer did not include the number of histologically positive nodes, valid comparisons could not be made with survival of women with breast cancer. This investigation was performed to produce a more reliable assessment of the prognosis of breast cancer in men. We analyzed clinical and pathologic data with particular attention to axillary nodes and tumor diameter.
Patients and Methods

As is common clinical practice, when a more serious or significant physical sign is recorded, a sign considered less serious often is unrecorded. Also, in instances in which patient status was reported by TNM classification, actual measurements might not be available. Each graph and table presented includes all patients with known information on the assessed parameters.

Analytic Methods
On univariable analysis, age, skin ulceration, clinical and histologic tumor diameter, and axillary node status were found to be significant prognostic factors. Other factors considered, but not found to be significant, were as follows: perinodal extension of tumor, skin and chest wall fixation, and histologic type. Survival analysis was performed with the BerksonGage method, as implemented in the Statistical Package for the Social Sciences X, version 9 (Evanston, IL). Differences between survival curves were tested by the Lee-Desu statistic.25Simultaneous assessment of multiple variables was pursued with the Cox proportional hazards regression.26 The proportional hazards assumption was assessed by stratification on each covariate in turn while including the other variables as factors in the Cox model. The log(-log) plots of the adjusted baseline survival function estimates for each stratum were roughly parallel. The linearity assumption for interval-scaled covariates was verified with the use of cubic spline functions.27We used the implementation of the Cox model as coded by the BMDP Statistical Software Package Program 2L (1990, Los Angeles, CA). Multivariable analysis was performed on factors that were significant on univariable analysis. Interaction terms between pairs of these variables were not significant. These factors were entered into three Cox proportional hazards models with clinical data and different end points for cause of death. A fourth model was used to calculate the relative risks based on pathologic data. Tumor size was coded as a continuous variable and is presented in the models as the effect of a 30-mm difference in diameter. The age of 65 years was the point that reflected the greatest difference in survival; therefore, age was dichotomized at 65 years. The number of positive nodes was grouped into three sets: none, one to three, and four or more. All other variables were analyzed as binary variables.
Results

Cancer centers participating in the International Patient Data Exchange System collect a common clinical data set on patients with cancer. Representatives from each center meet annually to maintain uniform data collection and quality control and to plan new studies. Their data bases were searched for male patients with breast cancer registered from January 1, 1965, through December 31, 1986. For patients to be eligible for the study, diagnoses had to be made within 3 months of registration and the patients had to have histologically confirmed carcinoma of the breast and receive part or all of their initial treatment at one of the participating institutions. There were 380 patients who met these criteria: Rotterdam, 69; Mt. Vernon, 55; Lund, 50; Houston, 49; Budapest, 43; Bordeaux, 39; Amsterdam, 17; Beijing, 17; Leiden, 15; Essen, 14; and Buffalo, 12. It should be mentioned that the number of patients from each participating center does not necessarily reflect its total case load of breast cancer cases in men. At some of the participating centers, most of the patient population will have completed initial cancer treatment before registration. Men with breast cancer who had prior treatment were not included in this study to avoid the biases introduced by analyzing patients who might have failed to respond to treatment at other hospitals. At each center, charts were reviewed during November and December 1988, with the use of a code sheet and corresponding coding manual. The cause of death was based on statements written in the medical record of the patient by the treating physician. If a death was not specified as resulting from breast cancer or another specified cause it was recorded that the cause was unknown. The study was coordinated by the Houston data center. Not all data items were available for each patient.

Patient Characteristics
Eleven patients with a diagnosis of in situ carcinoma of the breast and 26 patients with distant metastases were excluded from the analysis of prognostic factors. Eight

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CANCER fanuary 2, 2993, Volume 71, No. 1

others were excluded because pertinent clinical data were not recorded. The median age of the 335 patients included in the analysis was 63.0 years, with a range of 23-97 years (mean, 62.8 years). The most frequent histologic designations were adenocarcinoma (44.2%), ductal carcinoma (33.7%), and epithelial carcinoma, not otherwise specified (16.4%). The median follow-up of the entire study cohort (335 patients) was 52 months, with a mean of 65.4 months. There were 95 deaths resulting from breast cancer. Disease-specific survival analyses were based on deaths resulting from breast cancer, leading us to censor the survival time of 83 patients because of "death due to other causes." The patients in whom cancer was diagnosed before 1984 and who were still alive at last follow-up had a median follow-up of 89 months (mean, 99 months). Of the 42 living patients with recent diagnoses (1984-1986), 39 had current follow-up at the time of the study. There were 224 patients with reports of both clinical and histologic axillary findings. The number of nodes examined histologically ranged from 1 to 39, with a median of 8. Patients with negative nodes on histologic examination had a median of 9 nodes examined; patients with 1-3 positive nodes had a median of 6 examined; and patients with 4 or more positive lymph nodes had a median of 13 examined. Patients with negative clinical axillary findings had a median of nine nodes examined histologically. Patients with positive clinical axillary findings had a median of eight nodes examined. Three hundred eight of the 335 patients had surgery. Most patients (220) had a mastectomy with node dissection, 58 had mastectomy without node dissection, and 30 had a local excision. Most of these patients also had radiation therapy (245 of 308). Twenty-two of the 27 men who did not have surgery received radiation therapy. Three of the remaining five patients had chemotherapy or antiestrogen therapy alone or in combination. Two patients had no treatment after biopsy. Chemotherapy was used for 38 patients, and antiestrogen therapy was used in 25.

tion of survival because they also had distant metastases at presentation. For some patients, more than one physical finding was recorded. Among the 40 patients with chest wall fixation, 29 also had skin fixation. Of the 44 patients with skin ulceration, 10 also had chest wall fixation.

Tumor Dianieter
In 257 patients, the clinical tumor diameter was known. Patients with a clinical tumor diameter of 10 mm or less had a 94% 5-year survival rate (Table 1). For patients with a tumor diameter between 11 and 40 mm, the 5-year survival rate remained stable at approximately 80%. In patients with a tumor diameter larger than 40 mm, the 5-year survival rate decreased to approximately 40%.

Ten-Year Survival Rate by Clinical Node Status

The survival curve of patients with clinically positive axillary nodes shows a significantly poor prognosis ( P < 0.0001) when compared with the survival of patients with a clinically negative axilla (Fig. 2). The 10-year survival rate was 45% for patients with clinically positive axillary nodes and 69% for those with clinically negative axillary nodes. In our study, sufficient numbers of patients were available to allow calculation of valid survival curves beyond 5 years. At the beginning of the 6th year, 100 of the patients with clinically negative nodes were at risk, as were 47 with clinically positive nodes.

Ten-Year Survival Rate by Histologic Node Status

For the first 3 years after diagnosis, the survival curves of patients with one to three positive nodes and four or more positive nodes were the same (Fig. 3). At that point, the group with four or more positive nodes had a sharp decrease in survival. A similar decline in survival occurred at approximately 5 years in the patients with one to three histologically positive nodes. Survival at 10 years was 84% for patients with histologically negative nodes, 44% for those with one to three positive nodes, and 14% for the group with four or more histologically positive nodes. Beyond the fifth year, these survival curves were based on 102 patients who were at risk at the beginning of the sixth year. Of these, 53 had histologically negative nodes, 33 had one to three histologically positive nodes, and 16 were in the group with four or more histologically positive nodes. In the group of 56 patients with 4 or more histologically positive axillary nodes, 9 had 10 or more positive

Chest Wall and Skin lnvolvement

The patients who had tumor fixed to the chest wall (40) or skin (73) had essentially the same survival curves (Fig. 1) as those in whom fixation was absent ( P = 0.86 and P = 0.19, respectively). If ulceration was noted, there was an immediate decrease in survival (P < 0.0001). In the group of patients with ulceration, there were no deaths due to breast cancer after the fifth year. It should be mentioned that there were 11 patients with ulceration who were not included in this calcula-

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157

45% survival rate of those with clinically positive axillae.

80

Comparability of Patients Among Centers

To assess possible variation in the study population among institutions, data from the five centers with fewer than 20 patients were compared with the data from the six centers with more than 35 patients. The two groups of patients had essentially the same presentation of clinical and pathologic node status and pathologic tumor size. For example, 40% of patients from centers with fewer than 20 study subjects had palpable nodes versus 45% of patients from centers with more than 35 study subjects. Similarly, the percentages of patients with histologically negative nodes were 23% and 28%, respectively. The mean pathologic tumor diameter was 24 mm for each group. The two groups had overlapping survival curves, based on all deaths ( P = 0.36) and breast cancer-specific deaths ( P = 0.33).

5
2

40

2o

-0

t
2
4 5 6
8

1
10

Years From Dlagnosls

Figure 1. Disease-specific survival rate in 335 men with breast cancer according to skin involvement and chest wall fixation. -: No fixation (n = 178); - * - : skin fixation (n = 73); - - - -: chest fixation (n = 40); -- - -: skin ulceration (n = 44).

nodes. Eight of these had clinically positive axillae. Within 48 months, seven died of breast cancer and one of another cause. One patient, late on study, was alive on last contact at 26 months.

Multivariable AnaZysis of Prognostic Factors A series of Cox proportional hazards models was used to delineate the relative contribution of factors that are predictive of risk of death (Fig. 4).Both clinical axillary node status and clinical tumor diameter were predictive of death due to breast cancer (model 1).A patient with palpable axillary nodes had 2.14 times the risk of death due to breast cancer as a patient with a clinically negative axilla. An increase in tumor diameter of 30 mm carried a similar increase in risk (2.08). Eleven deaths were classified as resulting from an unknown cause. In the second model, these deaths were included as though they resulted from breast cancer. The relative risks remained approximately the same. In these models, which included information on the clinical axillary node status and clinical tumor diameter, skin ulceration did not represent significant additional risk for death due to breast cancer.

Five-Year Survival Rate b y Combined Axillary Node Status

The 94 patients with histologically negative nodes had a 90% 5-year survival rate (Table 2). The 5-year survival rate in those with one to three histologically positive nodes was 7383, and in those with four or more positive nodes it was only 55%. At each level of histologic node involvem,ent, patients with a clinically negative axillary status had a significantly better survival rate than patients who had clinically positive findings. Among the patients with four or more histologically positive nodes, those who had clinically negative axillae had a 5-year survival rate of 78%, in contrast to the

Table 1. Median Age, Skin Ulceration, Clinical Axillary Status, and 5-Year Disease-Specific Survival Rate According to Clinical Tumor Diameter
Clinical diameter (mm)
0-10 11-201 21-30 31-40 41-50 51+ Unknown Total

No.
23 87 55 38 26 28 78 335

Median age (yr)

55 62 65 62 66 66 61 63

Skin ulceration
4% 5% 15% 13% 23% 43% 11% 13%

Positive nodes
30% 39% 53% 45% 65% 71 y o 34% 45%

5-year survival rate

94 % 80% 78% 8 1 010 41% 39% 80% 76 %

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tumor diameter, but tumor size remained a significant prognostic factor in its own right.
Discussion

*O 0

10

With the benefit of a large study cohort, it was important for this study to confirm or revise observations on breast cancer in male patients drawn from smaller studies and to present our findings in sufficient detail so that comparisons with the data for breast cancer in women could be made. We evaluated skin and chest wall fixation, skin ulceration, tumor diameter, and clinical and histologic node status.

Years From Diagnosis

Figure 2. Disease-specific survival rate in 335 men with breast cancer according to clinical axillary status. -: Clinically negative (n = 185);- - -: clinically positive (n = 150) (P i 0.001).

Fixation
Fixation to the chest wall or skin has been reported freq~ently','~ in ,~ male ~ , ~ patients ~ with breast cancer. A few author^'^*^* have mentioned that the presence of skin and chest wall fixation would result in a shift of male patients to a less favorable prognostic stage. However, the question has remained: With a smaller amount of breast tissue in the male, does fixation carry the same prognostic significance as in the female? In our study, patients with reported chest wall fixation and skin fixation had a survival rate equivalent to that of patients without any type of fixation.

An analysis also was performed on the effect of the prognostic factors of breast cancer on all causes of death, including breast cancer. In this model, nodes and tumor size remained significant. In addition, age appeared to be a significant prognostic factor. Finally, in a fourth model, the risk of death due to breast cancer was measured for pathologic tumor size and number of histologically positive nodes. The risk for a patient with four or more positive nodes was 6.75 times that of a patient with histologically negative nodes. Similarly, a patient with one to three positive nodes had more than three times the risk of death. Histologic nodal status carried more risk than pathologic

Ulceration
Skin ulceration has been reported to be more frequent in male than female patients,'r3O associated with larger t~mors,~ and ~,~ linked ' to a poor p r o g n ~ s i s .In ~ , our ~~ study, ulceration was associated with a rapid decrease in survival on univariable analysis. However, in the proportional hazards analysis of the clinical findings, skin ulceration was overshadowed by axillary node status and tumor diameter. In the presence of these other

100

80

Table 2. Disease-Specific Survival Rate at 5 Years According to Clinical and Histologic Axillary Node Status for 224 Male Patients With Breast Cancer

2o 01 0

t
2 4 5 6
8

1
10

Histologic status Negative All positive 1-3 positive 4 f positive

Clinical axillary status All

90% 65% 73% 55% (94)t (130) (74) (56)

Negative
95% (71)

Positive
74% (23) 54% (79) 62Y0 (39) 45% (40)

P value*
0.0367 0.004 0.0287 0.0139

Years From Dlagnosls

81% (51)
84% (35) 78% (16)

Figure 3. Disease-specific survival rate in 224 men with breast cancer according to the number of histologically positive axillary lymph nodes (P < 0.0001). -: Negative (n = 94); - - -: 1-3 positive (n = 74); * * . - :4+ positive (n = 56) (1-3 versus 4 f ; P = 0.05).

* P values calculated for the one-sided hypothesis that the 5-year survival
rate is greater for patients with a negative clinical axillary status. t Number.

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Figure 4. Relative risk of death for male patients with breast cancer according to the Cox proportional hazards analysis of four alternative P values models. Bold boxes in<dicate of less than 0.05 and thin boxes indicate P values from1 0.05 to 0.20. Relative risks without boxes have P values greater than 0.120. *Coded in millimeters, shown as a relative risk of a 30-mm difference.

two factors, ulceration did not contribute significantly to prognosis.

Tumor Diameter
Larger tumor diameter has been associated with a poor survival rate.3,'5,32,.'3 In our study, the survival rate was better than in previous studies for each category of tumor diameter. In <contrastto reported 5-year survival rates of 44% or less among patients with measured tumor diameters of 21-50 mm,3,17 we found a steady 80% 5-year survival rate in patients with tumors in the 1140-mm range. The prospect of 5-year survival changed markedly at two points, at tumor diameters of 10 mm and 40 mm. In each of the ]proportional hazards models, clinical tumor diameter and clinical axillary status carried an approximately equal risk of death due to breast cancer. With the added specificity of pathologic examination, the risk associated with increased tumor diameter remained approximately the same (2.63), but the risk associated with the number of positive nodes increased appreciably. Similarly, in a recent large study of breast cancer in female patients, Carter et al.34indicated that the variation in relative survival at 5 years was much

greater between groups classified according to nodal status (negative, one to three positive nodes, and more than four positive nodes) than between groups classified according to tumor size.

Clinical Nodes
Although authors routinely comment that in breast cancer clinical axillary findings are inaccurate and misl e a d i r ~ g ,there ~~,~ can ~ be no question that there was a very clear difference in survival based on clinical assessment of the axilla in our study. The 10-year survival rate was 69% for patients with clinically negative nodes and 45% for those with clinically positive nodes. Previous large series reported that 10-year survival rates of patients with clinically negative nodes were in the 3848% r a ~ ~ g e . ~ , ' ~

Pa tho logic Nodes

The survival experience of our patients grouped by their overall histologic findings is similar to the results of Heller et a1.,16 in which there was a 90% 5-year survival rate for patients with negative nodes and a 59% rate for those with positive nodes. At 5 years, the sur-

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viva1 rates of our patients were 90% and 65% respectively. Our 84% 10-year survival rate for patients with histologically negative nodes is essentially the same as found by Hultborn et al.15 (81%) and Heller et al." (79%). Where our study differs is the further definition of histologically positive axillary node status into categories of one to three and four or more positive nodes. Our composite 5-year survival rate of 65% for those with positive nodes resulted from the combined experience of those with one to three positive nodes (a 73% survival rate) and four or more positive nodes (a 55% survival rate). The 10-year survival rate of male patients with histologically positive nodes has been reported in ~ ' our ~ study, patients with the range of 11%to 2 5 y 0 . ' ~In four or more positive nodes had only a 14% 10-year survival rate, but those with one to three positive nodes had a 44% 10-year survival rate. The dominant role of histologic node status in determining prognosis clearly was supported in the multivariable analysis. No reason has been given in other studies why histologically positive nodes were not subdivided in calculating survival. In most instances, the small numbers of patients studied probably would not have supported additional subdivision. Nevertheless, the fact that positive pathologic node findings were not subdivided certainly contributed to interstudy variations. Comparison with survival rates reported for female patients with breast cancer must allow for variation in time period, age, and study eligibility criteria. In addition, survival calculations have been reported as abso!Ute, relative, disease-specific, or not specified. With consideration of these factors, the survival rates at 5 and 10 years of the men with breast cancer in this study were comparable to those of the larger published series of female patients with breast ~ a n c e r . ~ For ~ -example, ~* among premenopausal and postmenopausal women, Fisher et aL40reported 5-year survival rates of 62% and 32% after radical mastectomy for patients with one to three and four or more positive nodes, respectively. At 10 years, the survival rates decreased to 37% and 13%, respectively, in the same groups.

mately half (35 of 74) had clinically negative axillae, whereas, of the patients with four or more histologically positive nodes, only one-fourth had clinically negative axillary findings (16 of 56).
Conclusions

In male patients with breast cancer, the prognostic importance of the number of histologically positive nodes was established. It is seen in the comparison of survival curves and supported by proportional hazards analysis. In multivariable analysis models, tumor size retained prognostic significance in the presence of either clinical or histologic axillary node findings. Finally, survival rates for breast cancer are the same for men and women when the number of histologically positive axillary nodes is considered.
References
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Breast Cancer in Males/Guinee ef al.

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