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A guide to the frequency of nipple involvement in breast cancer
A Guide to the Frequency of Nipple Involvement in Breast Cancer A Study of 149 Consecutive Mastectomies Using a Serial Subgross and Correlated Radiographic Technique
Michael D. Lagios, MD, San Francisco,
California
Elena A. Gates, BA, San Diego, California Philip R. Westdahl, MD, San Francisco, Victor Richards, MD, San Francisco,
California
California
Bernard S. Alpert, MD, San Francisco,
California
Preservation of the nipple and areola for breast reconstruction after mastectomy has been a subject of increasing interest [I ,2]. A major surgical consideration in nipple and areolar preservation as either a flap or a free graft is the potential for residual carcinoma within the nipple-areola complex. Previous studies of the likelihood of nipple involvement, citing frequencies of 8 to 12 per cent, have relied on conventional sampling of the nipple-areola complex or on retrospective review of previously submitted material. The relation of nipple involvement and the proximity of the primary tumor, alt.hough noted for tumors that were retroareolar, was not a principal object of study or quantitated in a reproducible way. The present study was designed to determine the t.ype and frequency of nipple involvement in a consecutive series of mastectomy specimens studied by t.he serial subgross and correlated radiographic method developed by Egan [3]. Particular attention was given to the concept of a mock nipple-areola graft in assessing relation t.he breast
the extent
of nipple
to size, histologic
aspects,
involvement
and its
and proximity
of
carcinoma.
Material and Methods All mastectomies performed at Children’s Hospital and Adult Medical (‘enter since July 1,1975 have been studied From the Departments of Pathology, Surgery, and Plastic Surgery, University of California and Children’s Hospital of San Francisco, San Francisco, California, and the University of California San Diego Medical School. San Diego. California. This work was supported in part by Grant No. PDT-106 from the American Cancer Societv. Inc. Reprint requests should be addiessed to Michael D. Lagios, MD, Department of Pathology, Children’s Hospital of San Francisco, 3700 California Street, San Francisco, California 94143. Presented at the 50th Annual Meeting of the Pacific Coast Surgical Association, Yosemite National Park, California, February 19-22. 1979.
Volume 138, July 1979
by a serial subgross and correlated radiographic method of examination. The 191 mastectomies performed in the
period July 1, 1975 to July 31,1978 were reviewed for this study. Forty-two cases were excluded for the following reasons: prior radiation therapy for inoperative breast cancer, 5 cases; prior partial mastectomy, 1; subcutaneous mastectomy, 5; inadequate sampling of the nipple-areola complex, 5; inability to confirm tumor diameter, 4; inability to review serial radiograms, 13; and an additional 9 cases could not be reviewed. The remaining 149 cases from this time period comprise the body of this study. Serial 2.5 mm thick segments of the mastectomy specimens were prepared as previously described [3,4] and correlated with their respective radiographic images to determine the distribution and extent of the carcinoma within the breast and the frequency of multicentricity. During the initial 18 months of the study representative segments of the serially sectioned nipple-areola complex with underlying subareolar stroma and breast parenchyma were sampled. Subsequently the nipple-areola complex was separated from the mastectomy specimen and serially embedded apart from the remainder of the breast. Carcinomatous involvement of the nipple-areola complex was classified as invasive and noninvasive, and nipples showing such involvement were designated invasive nipple and noninvasive nipple. Invasive involvement included infiltrating carcinoma within the dermis, subareolar stroma, or superficial 4 mm of subareolar fat. Lymphatic carcinomatosis involving the dermal or subareolar lymphatics was also included in this category. Noninvasive carcinoma included duct and lobular carcinoma in situ, Paget’s disease of the nipple-areola skin, and pagetoid involvement of distal lactiferous ducts. The anatomic area screened for carcinoma simulated a nipple-areolar graft and included the nipple and areolar epidermis, dermis, and subareolar st,roma and fat to a depth of 4 mm beneath the level of the areola. Proximity to the nipple-areola complex was confirmed with specimen radiography and serial sections of the breast.
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et al
TABLE I
TABLE II
Nipple Status
Status
No.
Per cent
Benign nipples Nipples with carcinoma Invasive Noninvasive
104
69.8
22 23
14.7 15.4
Subtotal Total
45 149
30.2 100
The closest distance was measured between the radiographic nipple margin and the tumor border in the specimen radiograph of the intact mastectomy specimen. The areolar margin could not be visualized radiographically in many breasts and thus could not be used as a reference point. In specimens in which the density of the breast precluded accurate assessment of the proximity of tumor margin to nipple based on radiographic examination, the determination was based on the distribution of the cancer within the breast on the basis of serial subgross examination [4]. Results Overall, 30.2 per cent of nipple-areola complexes were involved with carcinoma (Table I), nearly equally divided between invasive (22) and noninvasive cancer (23). This high frequency of carcinomatous nipple involvement was strongly correlated with the proximity of the tumor to the nipple border. Two groups can be separated on this basis: group I includes cancerous lesions that extend from within the nipple (not areolar) border to a distance of 25 mm (74 cases), and group II includes those greater than 25 mm distant from the nipple border (75) (Table II and
Correlation Between Nipple Involvement and Proximity of Tumor to Nipple Border
Nipple Status
Group I (O-25 mm)
Group II (26-100 mm)
Benign nipples Nipples with carcinoma Invasive Noninvasive
40 (38%)
64 (62%)
21 (95.4%) 13 (56.5%)
1(4.6%) 10 (43.5%)
Total
74
75
Total 104 (100%)
22 (100 %) 23 (100 %) 149
Figure 1). A distance of 25 mm from the nipple border was chosen because this figure would provide for a minimal diameter of 55 mm. This diameter would encompass the majority of nipple-areola complexes. As an approximation then, group I tumors would fall within the areolar margin and group II tumors beyond it. A large number of group I tumors involved the nipple (Figure 1) and are designated 0 mm. This large number includes both cases that directly underlay the nipple and those in which the radiographic tumor border only marginally contacted the nipple. Inoasiue Nipples. The majority (72 per cent) of the 22 nipples with invasive cafcinoma occurred in association with breast cancers that were subareolar and extended to the nipple border or within it. These subareolar lesions with invasive nipple involvement comprise 43 per cent of all subareolar carcinomas and 22 per cent of all group I lesions. Only a single case of invasive carcinoma involving the nipple complex occurred in group II. The latter represents 4.5 per cent of all invasive nipples and 1.3 per cent of all group II lesions. This lesion lay 35 mm from the
Figure 1. Distribution of carcinomas measured from the nipple border in millimeters. Solid black = invasive nipple; crosshatch = noninvasive nipple; blank = benign nipple.
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The American Journal Of Surgery
Nipple Involvement
TABLE III
Number and Relative Frequencies (Percentage)
in Breast
Cancer
of Histologic Types of Carcinoma
Duct Histologic Type
Noninvasive
Well
All Cases Invasive nipples Noninvasive
9 (6%) 0 2
13 (8.7%) 0 1
Mod 46 (31%) 2 (9%) 10 (43%)
Poor
LOB
TUB
Other
Total
52 (35 %) 15 (68%) 4 (22%)
16 4 3
6 0 0
7 1 3
149 (100%) 22 (100%) 23 (100%)
Duct = infiltrating ductal carcinoma; LOB = lobular infiltrating; Noninvasive = in situ carcinoma of duct and lobular type; Other includes medullary, colloid, and papillary invasive cancer; TUB = tubular carcinoma; Well, Mod, Poor, respectively = well, moderately and poorly differentiated.
nipple border and was a poorly differentiated duct cancer. Thus, the relative ‘difference in frequencies between invasive nipples in group I and II is 22fold. The degree of differentiation of the reference carcinoma also appears related to the likelihood of nipple involvement by carcinoma. Among invasive nipples, the reference carcinoma was poorly differentiated ductal carcinoma in 68 per cent, nearly twice the overall frequency of that histologic type (Table III) among the study cases. This tendency was most clearly demonstrated among those tumors that did not directly involve the nipple but extended 1 to 25 mm from the nipple border, in which all five invasive nipples were associated with a poorly differentiated ductal carcinoma. The association of poorly differentiated ductal carcinoma and noninvasive nipples was, in contrast, quite low; only 21 per cent of noninvasive nipples (5 of 23) were so associated. Involvement of the nipple was more frequent in patients with axillary metastases than in those without metastases (56 versus 31 per cent). This was particularly true for invasive nipples in which the frequency of axillary metastases was 72 per cent, more than twice that of cases with benign nipples (Table IV). However, this higher frequency is associated with a greater tumor diameter in the group with invasive nipples. Noninvasive Nipples. In contrast to nipple involvement by invasive carcinoma, there was little evidence for an association between the proximity of the tumor to the nipple border and the likelihood of noninvasive cancer within the nipple. The frequency of such involvement was 17.5 and 13.3 per cent, respectively, for the tumor groups I and II. The most common type of involvement by noninvasive cancer was subclinical, microscopic pagetoid involvement of a lactiferous duct. This was often associated with Paget’s disease limited to the cutaneous surface immediately adjacent to the opening of a lactiferous duct and in two instances was also associated with lobular carcinoma in situ (Table V). Ductal carcinoma in situ alone, involving either a lactiferous duct
Volume 139, July 1979
TABLE IV
Group
Number of Cases with Axillary Metastases in Relation to Nipple Status Among 129 Mastectomy Specimens With Axillary Dissection”
Benign Nipple
Invasive Nipple
Noninvasive Nipple
I II
11132 17158
12117 l/l
7111 3110
Total
28190 (31%)
13118 (72%)
s/21 (43%)
Frequency of axillary metastases in combined carcinomatous nipples, 22139 (56 per cent); benign nipples; 28190 (31 per cent): all study cases, 501129 (39 per cent). l
TABLE V
Histologic Type of Noninvaslve Nipple Involvement
Involvement Pagetoid only Paget’s and pagetoid Paget’s, pagetoid, and LCIS Subtotal for pagetoid group DCIS Total
Group I
Group II
5 1
3 1
8 2
0
2
2
6
6
7 13 (57 %)
4 10 (43%)
Total
12 (52 %) 11 (48 %) 23 (100%)
DCIS = duct carcinoma in situ with or without other noninvasive lesions; LCIS = lobular carcinoma in situ; pagetoid = pagetoid change involving lactiferous duct; Paget’s = Paget’s disease of nipple.
or a lobule within the nipple stroma, occurred in 11 instances. Lobular carcinoma in situ did not occur as a separate lesion in this series. Paget’s disease with or without other noninvasive lesions within the nipple occurred in 4 of 23 cases. Three additional cases occurred among the invasive nipples. The overall frequency of Paget’s disease was 4.7 per cent. Only one of the seven cases was recognized clinically. Tumor Diameter. Maximum diameter of the invasive components of the carcinoma was determined
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Lagios et al
TABLE VI
Average Diameters of Invasive Tumor Mass* and Numbers Greater and Less Than 2 cm Diameters (mm)
Nipple Status
Group
Invasive nipple Noninvasive nipple Benign nipple
36 22 20
I
Numbers
Group II
Average of I and II
<2 Cm
25 15 19
35 19 19
6 14 60
>2Cm 16 7 35
* Excludes nine noninvasive cancerous lesions.
TABLE VII
Multicentricity of Carcinoma
Nipple Status
Multicentric
Invasive nipple Noninvasive nipple Benign nipple
5 (23 %) 8 (35%) 18 (17%)
Total
31 (21%)
TABLE VIII
Unicentric 17 (77%) 15 (65 %) 86 (83%) 118 (79%)
Total 22 (100%) 23 (100%) 104 (100%) 149 (100%)
Clinically Recognized Nipple Involvement
Involvement All carcinomatous nipples Invasive nipples Noninvasive nipples
Total Cases
No. Clinically Abnormal
45
12 (26.6 %)
22 23
11 (50.0 %) 1 ( 4.3 %)
as described previously [4]. The cancers associated with invasive nipples were, on the average, nearly twice as large as those associated with either noninvasive or benign nipples (Table VI). This difference was significant at the 0.01 level by chi square analysis. There was no significant difference in average tumor diameters between group I and group II cases among noninvasive or benign nipple associated cancers. The average diameters of the lesion in groups I and II irrespective of nipple involvement were 24.5 and 18.3 mm, respectively, but this difference is not significant. However, on the average, the largest tumors did fall into the subgroup of the 37 group I lesions that were directly subareolar with an average diameter of 29.7 mm as compared to the 1 to 25 mm distant subgroup with an average diameter of 19.4 mm. Mukicentricity. The overall frequency of multicentric foci of carcinoma among the 149 mastectomies was 20.8 per cent (31 cases). Multicentricity was defined as previously [4]. The frequency of multicentricity among cases of nipple involvement of any type, 28.8 per cent (13 of 45), was higher than that among cases of benign nipples, 17.3 per cent (18 of 104), but these differences were not significant by chi square analysis (Table VII).
138
Clinical Recognition of Nipple Involvement. Twelve of 45 carcinomatous nipples were recognized as clinically abnormal (26.6 per cent). In 11 cases the nipple was fixed, indurated, or both, and in these infiltrating carcinoma was identified in the nipple stroma. The tumor lay directly under the nipple in nine, and in the two remaining cases the nearest radiographic tumor borders were 15 and 16 mm distant. A single case with a crusted nipple surface represented Paget’s disease (Table VIII). In summary, clinical inspection of the nipple identified an abnormality consistent with invasive involvement in half the invasive nipples. The remaining half of the invasive nipples were without clinically described abnormality but had a similar distribution of carcinoma. The latter were located beneath the nipple in seven cases, and in single instances at 5,10,25, and 35 mm distant. Clinical recognition of noninvasive carcinoma was poor; only 1 of 23 cases was identified as abnormal (4.3 per cent). This single case represented Paget’s disease of the nipple but was the only one of seven cases of Paget’s disease so recognized. Comments Three factors amenable to clinical evaluation are associated with a high frequency of nipple involvement by biologically more significant invasive carcinoma and appear useful in estimating the likelihood of nipple involvement. 1. Proximity of the tumor mass: In this study 95 per cent of all invasive nipples were associated with tumors that lay within 25 mm of the nipple margin, with a single exception at 35 mm. As noted previously [5-71, most of these tumors lay directly under the nipple or had a radiographic tumor border that extended to it, although 23 per cent of all cases of invasive nipple involvement were associated with more distant tumors. Proximity of the tumor to the nipple border appears to be the most reliable factor in predicting involvement by invasive cancer. 2. Tumor size: Involvement of the nipple by invasive carcinoma was significantly associated with
The American Journal of Surgery
Nipple
TABLE
IX
involvement
in Breast
Cancer
Comparative Relative Frequencies and Types of Nipple Involvement (per cent) Fisher et al (1975)
Invasive Infiltrating Lymphatic Noninvasive Paget’s or pagetoid In situ Total Overall frequency of carcinomatous nipple (per cent) Frequency of invasive nipple involvement
52.0 526 47.6 11.0 36.4 100 11.1 (107/967)
5.8
the maximum diameter of the invasive tumor mass. The average diameter of tumors associated with invasive nipples was 35 mm compared to an average of 19 mm for tumors associated with either noninvasive or benign nipples. Seventy-three per cent of all cases of invasive nipple involvement were associated with tumors greater than 2 cm in diameter (Table VI). This frequency is significantly different from that for noninvasive and benign nipple associated cancers (p = 0.01 and 0.1, respectively). S. Clinical nipple abnormality: In contrast to the foregoing factors, clinically recognizable changes suspicious of invasive involvement of the nipple, induration, fixation, and peau d’orange were present in only half the invasive nipples, despite a similar distribution of lesions within the breast among those with and without clinical abnormality of the nipple. This rather large unassessed carcinomatous involvement more closely parallels the data of Smith et al [6], in which only 31 of 66 nipples showed a clinical abnormality, than of Parry et al [ 71, in which 14 of 16 were abnormal. It should be emphasized, however, that although only half the nipples were recognized as abnormal, all those that were so recognized contained invasive cancer. A fourth factor amenable to preevaluation in a two-stage biopsy procedure is the degree of differentiation of the tumor. As noted previously [6,7], poorly differentiated ductal carcinomas are more frequently associated with invasive nipple involvement. In this study 68 per cent of all invasive nipples contained poorly differentiated ductal carcinoma, nearly twice the overall frequency of this tumor type in the series. Significantly, this was the only tumor type associated with invasive nipples in those cases in which the primary tumor was not directly beneath the nipple: the five invasive nipples between 1 and 25 mm and the single case at 35 mm were all associated with poorly differentiated ductal carcinoma.
Volume 139,July 1979
Smith et al (1976)
100
68.1 54.5 13.6 31.9 15.2 16.7
Excluded 100
100 12.2 (66/541)
a.3
Parry et al (1977)
8 (161200)
100
Present Studv 48.8 46.6 2.2 51.1 26.6 24.4 100 30.2 (451149)
14.7
The 30 per cent relative frequency of nipple involvement documented in this study is substantially greater than the range of 8 to 12 per cent noted previously. This represents both invasive and noninvasive involvement in a ratio similar to that noted in previous studies [5,6] (Table IX), but the present 14.6 per cent frequency of invasive involvement is nearly twice that of Smith et al [6]. This higher frequency probably reflects the more directed and extensive sampling of the nipple-areola complex incident to the Egan serial subgross technique. Most of the noninvasive nipple involvement was represented by microscopic, subclinical Paget’s disease and associated changes in lactiferous ducts. The significance of these incidental microscopic lesions in the nipple remaining after subcutaneous mastectomy or breast reconstruction has not been assessed prospectively. Such noninvasive lesions showed no substantial differences in frequency related to the proximity of the carcinoma to the nipple nor are they likely to be recognized clinically. However, the location of these noninvasive lesions was such that virtually all of them would have been excluded from the nipple after excision of a central core of nipple stroma and skin as part of a nipple-areola skeletonization procedure. Two recent case reports document the problems inherent in nipple transplantation. One report [8] describes the case of a nipple graft in the groin which was removed when the patient elected not to undergo breast reconstruction. Examination of the removed nipple revealed infiltrating lobular carcinoma. The primary tumor in this case measured 5 to 6 cm in diameter and was associated with two lymph node metastases, and carcinoma was present in sections taken from beneath the nipple. From the data we generated in the present study, breast reconstruction with nipple preservation would not have been considered for this patient. A second report [9] described
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Lagios et al
inguinal lymph node metastases of a poorly differentiated ductal carcinoma which developed after autotransplantation of a free nipple graft to the groin. The primary carcinoma in this case is described as a multifocal infiltrating ductal carcinoma with lymphatic invasion and lymph node metastases. Although the size and proximity of the tumor to the nipple cannot be ascertained, intraductal carcinoma was noted in the nipple bed not far from the cut surface. This case cannot clearly be evaluated in terms of the recommendations developed from the present study although the poorly differentiated histologic aspects of the inguinal metastasis, the multifocal infiltrating pattern of the primary tumor, and its lymphatic and axillary lymph node involvement suggest that this patient would not have fallen into the group for which breast reconstruction and nipple preservation would have been considered. Although the likelihood of invasive cancer in a nipple can be estimated with some confidence, noninvasive cancer within the nipple, albeit of unknown portent, cannot be similarly estimated from the data presently available. Summary Based on a serial subgross and correlated radiographic examination technique, the frequency of carcinomatous involvement of the nipple was found to be 30.2 per cent in a consecutive series of 149 mastectomy specimens. This is significantly higher than that in other reported series. Carcinomatous nipple changes in this series were equally divided between invasive and noninvasive types. The most common type of noninvasive cancer found was subclinical, microscopic pagetoid involvement of a lactiferous duct and associated microscopic Paget’s disease of the skin of the nipple. Of the nipples with invasive carcinoma, 95.4 per cent were associated with primary tumors less than 25 mm from the nipple. Invasive nipples were more likely to be associated with primary tumors that were poorly differentiated, greater than 20 mm in diameter, and contained axillary metastases than were benign or noninvasive nipples. Fifty per cent of nipples with invasive changes had macroscopic clinical abnormalities. There appeared to be no way to predict the presence of noninvasive carcinomatous involvement of a nipple other than by thorough direct sampling. The associated primary tumor locations were evenly distributed, and only 4.3 per cent of nipples involved with noninvasive cancer were clinically evident.
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However, removal of the nipple per se and skeletonization of the remaining areola would virtually eliminate the chance of residual noninvasive carcinoma. The higher incidence of nipple-areolar involvement in breast carcinoma found in this series compared to previous reports probably reflects the sampling technique. These data should be considered when approaching the problem of mastectomy and potential reconstruction for carcinoma of the breast. They are not to be interpreted to mean that the investigators are advocates of the procedure. References 1. Millard DR Jr, Devine J Jr, Warren WD: Breast reconstructions: a plea for saving the uninvolved nipple. Am J Surg 122: 763, 1971. 2. Millard DR Jr: Nipple and areola reconstruction by split-skin graft from the normal side. Plasf Reconsfr Surg 50: 350, 1972. 3. Egan RL, Ellis JT, Powell RW: Team approach to the study of diseases of the breast. dncer 23: 847, 1969. 4. Lagios MD: Multicentricity of breast carcinoma demonstrated by routine correlated serial subgross and radiographic examination. Cancer 40: 1726, 1977. 5. Fisher ER, Gregorio RM, Fisher B: The pathology of invasive breast cancer. A syllabus derived from findings of the National Surgical Adjuvant Breast Project (Protocol No. 4). Cancer 36: 1, 1975. 6. Smith J, Payne WS, Carney JA: Involvement of the nipple and areola in carcinoma of the breast. Surg Gynec Obsfet 143: 546, 1976. 7. Parry RG, Cochran TC Jr, Wolfort FG: When is there nipple involvement in carcinoma of the breast. Plast Reconsfr Surg 59: 535, 1977. 8. Allison AB, Howorth MB Jr: Carcinoma in a nipple preserved by heterotopic auto-implantation. N Engl J Med 298: 1132, 1978. 9. Bouvier B: Problems in breast reconstruction. MedJ Aust 1: 937, 1977.
Discussion John M. Goin (Los Angeles, CA): This exceptionally important work has many implications, particularly in breast reconstruction after mastectomy. One earlier report of 200 breasts showed that only 8 per cent had microscopic evidence of cancer in the nipple, and of these 16 nipples, only 2 looked grossly normal. The present paper, reflecting a closer and more sophisticated scrutiny, shows that only half the nipples containing invasive carcinoma could be recognized clinically. One of the major implications of this work is that if there is a significant chance of transmitting cancer by nipple banking, the procedure has to be abandoned. There are two reports of transplantation of cancer to the groin via a banked nipple. Careful study of these reports shows that carcinoma was present in or not far from the sections taken from beneath the removed nipple. In one case the cancerous lesion was very large, 5 to 6 cm in size. In the other report, tumor size was not mentioned.
The American Journal of Surgery
Nipple Involvement
It seems clear, however, from the scanty information available that neither nipple should have been preserved. The data just presented suggests that nipples can be banked with considerable confidence when the nipple is normal in appearance and the primary tumor is well differentiated, smaller than 1.9 cm, and located more than 3.5 cm from the nipple margin. I would add to these criteria negative frozen section examination of both the subareolar breast tissue and a core from the interior of the nipple itself. Smith, Paine, and Carney in a similar study also concluded that when the nipple-areolar complex is clinically normal and the tumor is smaller than 2 cm and not situated behind the nipple, nipple involvement by carcinoma is rare. Virtually all$f the noninvasive nipple lesions could have been avoided by transplantation of only the areola, although the subsequent importance of these microscopic changes in the clinical course of the patient is not entirely clear. The use of an areolar graft alone does not seriously compromise the quality of reconstruction since nipple protrusion in an areolar graft can be simulated with implanted disks of auricular cartilage or composite ear lobe graft.s. For the truly fastidious, even the tubercles of Montgomery can be mimicked by tiny cartilage grafts scattered beneath the areolar graft. Ironically, as the bases for nipple banking have become more scientific, enthusiasm for the procedure has somewhat waned. Any free graft, including a banked nipple, that is transferred twice develops fibrosis and pigmentary changes that lead to a less than elegant result. Consequently, a number of new and ingenious methods of nipple reconstruction have been developed that some plastic surgeons believe have reduced the need for nipple banking. Pigmented skin from the upper thigh and perineum has also been used as well as retroauricular skin. Tom Cronin, an ingenious plastic surgeon from Houston, has even reconstructed nipples with hemorrhoids. The real problem is making two nipples that look alike. Nipple banking probably comes closer to this goal than any other method when only one breast is operated on. When it is necessary to operate on the other breast as well, whether to remove it for premalignant disease or to alter it for symmetry, satisfactory bilateral nipple reconstruction can almost always he accomplished by sharing the remaining nipple-areolar complex between the two breasts. Leon Morgenstern (Los Angeles, CA): In 1975 I reported to this Association a study on the multicentricity of breast carcinoma based on a review of 500 consecutive cases. Part of that study related to nipple involvement as a type of multicentricity. Nipple involvement occurred in 12.5 per cent of our multicentric lesions, or 5 per cent of the total series. We excluded all cases in which primary tumors
Volume
138,July
1979
in Breast Cancer
were contiguous with the nipple, and all our cases of nipple involvement were unsuspected on clinical grounds. Moreover, most were associated with tumors more than 25 mm distant from the nipple. Whether the incidence of nipple involvement is 5 per cent, as reported in our series, 8 to 12 per cent as reported elsewhere, or the astounding 30.2 per cent described in this series, the basic question is the meaning of this finding relative to nipple salvage for reconstruction. I firmly believe that if there is even a remote chance of transplanting tumor cells, and all these studies not only strongly suggest hut also prove that possibility, then this is an unacceptable practice in tumor surgery. Already in 1978 one instance of carcinoma has been described in a nipple preserved by heterotopic autotransplantation. Anecdotal reports grow to become series. I have little doubt that the preserved nipple-areolar complex, however salvaged in patients with carcinoma, will eventually cause transplantation of tumor cells in some persons. “Virtual” elimination of this risk is not a reasonable way to deal with carcinoma. Donald L. Morton (Los Angeles, CA): This study points out the frequency of histologic involvement of the nipple. My conclusion is that nipple autotransplantation is a lot of gobbledygook. If you can find histologic evidence of cancer in 30 per cent of nipples, doesn’t that mean that biologic cancer is there more frequently? How many times have we performed cancer surgery and had the pathologist report negative margins only to have recurrence? Histopathologic involvement usually underestimates the biologic recurrence rate. Therefore, it is wrong to save a nipple that is potentially involved with cancer. The patient is coming to you for treatment of cancer of the breast. Your first obligation is to treat that cancer properly, and to put the patient at risk of autotransplantation of tumor cells to a distant site, as well as hack to the same site so that she may have a more normal appearing nipple, to me is ridiculous and I just cannot accept it. Perhaps I have been privileged by working with a very talented group of plastic surgeons, hut Drs. Zarem and Miller and the group at UCLA effect a very respectable nipple from vulvar skin, and, in fact, some of our patients do not bother to wear bras after reconstruction. Therefore, to employ a procedure that exposes a patient to the danger of implantation of cancer cells just does not make good surgical sense when there are alternatives. While I have the opportunity, I might ment,ion another mistake in the management of breast disease which we are seeing more frequently and which involves patients who have had so-called subcutaneous mastectomy as a cancer-preventing operation. We have had a number of these women in our clinic who present within 2 or 3 years with cancer of the breast after this subcutaneous operation. Unfortunately, subcutaneous mastectomy is not total mastectomy, and cancer of the breast may still develop. There is no good information on whether this procedure prevents breast cancer, and although this operation may
141
Lagios et al
theoretically be appealing, we really must be careful before proceeding with subcutaneous mastectomy as a cancer preventive until we have some evidence of its effectiveness. Philip R. Westdahl (closing): Our purpose in presenting this study was not to advocate this procedure. This study was undertaken to find an accurate means of determining when the nipple-areolar complex might be involved, hoping thereby to discourage the procedure when it obviously should never be considered in the first place. Dr. Goin referred to those patients. We also wished to determine when it might be considered safe for those patients who might have a compelling desire for breast reconstruction. Dr. Lagios is to be commended on the thoroughness of his project. I still consider myself a cancer surgeon, not a plastic
142
surgeon. However, patients have heard about this procedure and some of them ask about it. They want to know everything possible about what can be done for them before mastectomy is undertaken. This study has enabled me to be more factual in discussing breast reconstruction with such patients. I do not disagree at all with Drs. Morgenstern and Morton. I believe, as they do, that the primary purpose of a cancer operation is to remove the local disease, and that preserving the nipple is a secondary consideration. Dr. Goin has described additional sources for reconstruction of the nipple. This study may also help us to better evaluate the efficacy of subcutaneous mastectomy as a prophylactic procedure in advanced mammary dysplasia or in very high risk patients and as a therapeutic procedure in patients with microscopic foci of carcinoma in situ.
The American Journal of Surgery
Michael D. Lagios, MD, San Francisco,
California
Elena A. Gates, BA, San Diego, California Philip R. Westdahl, MD, San Francisco, Victor Richards, MD, San Francisco,
California
California
Bernard S. Alpert, MD, San Francisco,
California
Preservation of the nipple and areola for breast reconstruction after mastectomy has been a subject of increasing interest [I ,2]. A major surgical consideration in nipple and areolar preservation as either a flap or a free graft is the potential for residual carcinoma within the nipple-areola complex. Previous studies of the likelihood of nipple involvement, citing frequencies of 8 to 12 per cent, have relied on conventional sampling of the nipple-areola complex or on retrospective review of previously submitted material. The relation of nipple involvement and the proximity of the primary tumor, alt.hough noted for tumors that were retroareolar, was not a principal object of study or quantitated in a reproducible way. The present study was designed to determine the t.ype and frequency of nipple involvement in a consecutive series of mastectomy specimens studied by t.he serial subgross and correlated radiographic method developed by Egan [3]. Particular attention was given to the concept of a mock nipple-areola graft in assessing relation t.he breast
the extent
of nipple
to size, histologic
aspects,
involvement
and its
and proximity
of
carcinoma.
Material and Methods All mastectomies performed at Children’s Hospital and Adult Medical (‘enter since July 1,1975 have been studied From the Departments of Pathology, Surgery, and Plastic Surgery, University of California and Children’s Hospital of San Francisco, San Francisco, California, and the University of California San Diego Medical School. San Diego. California. This work was supported in part by Grant No. PDT-106 from the American Cancer Societv. Inc. Reprint requests should be addiessed to Michael D. Lagios, MD, Department of Pathology, Children’s Hospital of San Francisco, 3700 California Street, San Francisco, California 94143. Presented at the 50th Annual Meeting of the Pacific Coast Surgical Association, Yosemite National Park, California, February 19-22. 1979.
Volume 138, July 1979
by a serial subgross and correlated radiographic method of examination. The 191 mastectomies performed in the
period July 1, 1975 to July 31,1978 were reviewed for this study. Forty-two cases were excluded for the following reasons: prior radiation therapy for inoperative breast cancer, 5 cases; prior partial mastectomy, 1; subcutaneous mastectomy, 5; inadequate sampling of the nipple-areola complex, 5; inability to confirm tumor diameter, 4; inability to review serial radiograms, 13; and an additional 9 cases could not be reviewed. The remaining 149 cases from this time period comprise the body of this study. Serial 2.5 mm thick segments of the mastectomy specimens were prepared as previously described [3,4] and correlated with their respective radiographic images to determine the distribution and extent of the carcinoma within the breast and the frequency of multicentricity. During the initial 18 months of the study representative segments of the serially sectioned nipple-areola complex with underlying subareolar stroma and breast parenchyma were sampled. Subsequently the nipple-areola complex was separated from the mastectomy specimen and serially embedded apart from the remainder of the breast. Carcinomatous involvement of the nipple-areola complex was classified as invasive and noninvasive, and nipples showing such involvement were designated invasive nipple and noninvasive nipple. Invasive involvement included infiltrating carcinoma within the dermis, subareolar stroma, or superficial 4 mm of subareolar fat. Lymphatic carcinomatosis involving the dermal or subareolar lymphatics was also included in this category. Noninvasive carcinoma included duct and lobular carcinoma in situ, Paget’s disease of the nipple-areola skin, and pagetoid involvement of distal lactiferous ducts. The anatomic area screened for carcinoma simulated a nipple-areolar graft and included the nipple and areolar epidermis, dermis, and subareolar st,roma and fat to a depth of 4 mm beneath the level of the areola. Proximity to the nipple-areola complex was confirmed with specimen radiography and serial sections of the breast.
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TABLE I
TABLE II
Nipple Status
Status
No.
Per cent
Benign nipples Nipples with carcinoma Invasive Noninvasive
104
69.8
22 23
14.7 15.4
Subtotal Total
45 149
30.2 100
The closest distance was measured between the radiographic nipple margin and the tumor border in the specimen radiograph of the intact mastectomy specimen. The areolar margin could not be visualized radiographically in many breasts and thus could not be used as a reference point. In specimens in which the density of the breast precluded accurate assessment of the proximity of tumor margin to nipple based on radiographic examination, the determination was based on the distribution of the cancer within the breast on the basis of serial subgross examination [4]. Results Overall, 30.2 per cent of nipple-areola complexes were involved with carcinoma (Table I), nearly equally divided between invasive (22) and noninvasive cancer (23). This high frequency of carcinomatous nipple involvement was strongly correlated with the proximity of the tumor to the nipple border. Two groups can be separated on this basis: group I includes cancerous lesions that extend from within the nipple (not areolar) border to a distance of 25 mm (74 cases), and group II includes those greater than 25 mm distant from the nipple border (75) (Table II and
Correlation Between Nipple Involvement and Proximity of Tumor to Nipple Border
Nipple Status
Group I (O-25 mm)
Group II (26-100 mm)
Benign nipples Nipples with carcinoma Invasive Noninvasive
40 (38%)
64 (62%)
21 (95.4%) 13 (56.5%)
1(4.6%) 10 (43.5%)
Total
74
75
Total 104 (100%)
22 (100 %) 23 (100 %) 149
Figure 1). A distance of 25 mm from the nipple border was chosen because this figure would provide for a minimal diameter of 55 mm. This diameter would encompass the majority of nipple-areola complexes. As an approximation then, group I tumors would fall within the areolar margin and group II tumors beyond it. A large number of group I tumors involved the nipple (Figure 1) and are designated 0 mm. This large number includes both cases that directly underlay the nipple and those in which the radiographic tumor border only marginally contacted the nipple. Inoasiue Nipples. The majority (72 per cent) of the 22 nipples with invasive cafcinoma occurred in association with breast cancers that were subareolar and extended to the nipple border or within it. These subareolar lesions with invasive nipple involvement comprise 43 per cent of all subareolar carcinomas and 22 per cent of all group I lesions. Only a single case of invasive carcinoma involving the nipple complex occurred in group II. The latter represents 4.5 per cent of all invasive nipples and 1.3 per cent of all group II lesions. This lesion lay 35 mm from the
Figure 1. Distribution of carcinomas measured from the nipple border in millimeters. Solid black = invasive nipple; crosshatch = noninvasive nipple; blank = benign nipple.
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The American Journal Of Surgery
Nipple Involvement
TABLE III
Number and Relative Frequencies (Percentage)
in Breast
Cancer
of Histologic Types of Carcinoma
Duct Histologic Type
Noninvasive
Well
All Cases Invasive nipples Noninvasive
9 (6%) 0 2
13 (8.7%) 0 1
Mod 46 (31%) 2 (9%) 10 (43%)
Poor
LOB
TUB
Other
Total
52 (35 %) 15 (68%) 4 (22%)
16 4 3
6 0 0
7 1 3
149 (100%) 22 (100%) 23 (100%)
Duct = infiltrating ductal carcinoma; LOB = lobular infiltrating; Noninvasive = in situ carcinoma of duct and lobular type; Other includes medullary, colloid, and papillary invasive cancer; TUB = tubular carcinoma; Well, Mod, Poor, respectively = well, moderately and poorly differentiated.
nipple border and was a poorly differentiated duct cancer. Thus, the relative ‘difference in frequencies between invasive nipples in group I and II is 22fold. The degree of differentiation of the reference carcinoma also appears related to the likelihood of nipple involvement by carcinoma. Among invasive nipples, the reference carcinoma was poorly differentiated ductal carcinoma in 68 per cent, nearly twice the overall frequency of that histologic type (Table III) among the study cases. This tendency was most clearly demonstrated among those tumors that did not directly involve the nipple but extended 1 to 25 mm from the nipple border, in which all five invasive nipples were associated with a poorly differentiated ductal carcinoma. The association of poorly differentiated ductal carcinoma and noninvasive nipples was, in contrast, quite low; only 21 per cent of noninvasive nipples (5 of 23) were so associated. Involvement of the nipple was more frequent in patients with axillary metastases than in those without metastases (56 versus 31 per cent). This was particularly true for invasive nipples in which the frequency of axillary metastases was 72 per cent, more than twice that of cases with benign nipples (Table IV). However, this higher frequency is associated with a greater tumor diameter in the group with invasive nipples. Noninvasive Nipples. In contrast to nipple involvement by invasive carcinoma, there was little evidence for an association between the proximity of the tumor to the nipple border and the likelihood of noninvasive cancer within the nipple. The frequency of such involvement was 17.5 and 13.3 per cent, respectively, for the tumor groups I and II. The most common type of involvement by noninvasive cancer was subclinical, microscopic pagetoid involvement of a lactiferous duct. This was often associated with Paget’s disease limited to the cutaneous surface immediately adjacent to the opening of a lactiferous duct and in two instances was also associated with lobular carcinoma in situ (Table V). Ductal carcinoma in situ alone, involving either a lactiferous duct
Volume 139, July 1979
TABLE IV
Group
Number of Cases with Axillary Metastases in Relation to Nipple Status Among 129 Mastectomy Specimens With Axillary Dissection”
Benign Nipple
Invasive Nipple
Noninvasive Nipple
I II
11132 17158
12117 l/l
7111 3110
Total
28190 (31%)
13118 (72%)
s/21 (43%)
Frequency of axillary metastases in combined carcinomatous nipples, 22139 (56 per cent); benign nipples; 28190 (31 per cent): all study cases, 501129 (39 per cent). l
TABLE V
Histologic Type of Noninvaslve Nipple Involvement
Involvement Pagetoid only Paget’s and pagetoid Paget’s, pagetoid, and LCIS Subtotal for pagetoid group DCIS Total
Group I
Group II
5 1
3 1
8 2
0
2
2
6
6
7 13 (57 %)
4 10 (43%)
Total
12 (52 %) 11 (48 %) 23 (100%)
DCIS = duct carcinoma in situ with or without other noninvasive lesions; LCIS = lobular carcinoma in situ; pagetoid = pagetoid change involving lactiferous duct; Paget’s = Paget’s disease of nipple.
or a lobule within the nipple stroma, occurred in 11 instances. Lobular carcinoma in situ did not occur as a separate lesion in this series. Paget’s disease with or without other noninvasive lesions within the nipple occurred in 4 of 23 cases. Three additional cases occurred among the invasive nipples. The overall frequency of Paget’s disease was 4.7 per cent. Only one of the seven cases was recognized clinically. Tumor Diameter. Maximum diameter of the invasive components of the carcinoma was determined
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TABLE VI
Average Diameters of Invasive Tumor Mass* and Numbers Greater and Less Than 2 cm Diameters (mm)
Nipple Status
Group
Invasive nipple Noninvasive nipple Benign nipple
36 22 20
I
Numbers
Group II
Average of I and II
<2 Cm
25 15 19
35 19 19
6 14 60
>2Cm 16 7 35
* Excludes nine noninvasive cancerous lesions.
TABLE VII
Multicentricity of Carcinoma
Nipple Status
Multicentric
Invasive nipple Noninvasive nipple Benign nipple
5 (23 %) 8 (35%) 18 (17%)
Total
31 (21%)
TABLE VIII
Unicentric 17 (77%) 15 (65 %) 86 (83%) 118 (79%)
Total 22 (100%) 23 (100%) 104 (100%) 149 (100%)
Clinically Recognized Nipple Involvement
Involvement All carcinomatous nipples Invasive nipples Noninvasive nipples
Total Cases
No. Clinically Abnormal
45
12 (26.6 %)
22 23
11 (50.0 %) 1 ( 4.3 %)
as described previously [4]. The cancers associated with invasive nipples were, on the average, nearly twice as large as those associated with either noninvasive or benign nipples (Table VI). This difference was significant at the 0.01 level by chi square analysis. There was no significant difference in average tumor diameters between group I and group II cases among noninvasive or benign nipple associated cancers. The average diameters of the lesion in groups I and II irrespective of nipple involvement were 24.5 and 18.3 mm, respectively, but this difference is not significant. However, on the average, the largest tumors did fall into the subgroup of the 37 group I lesions that were directly subareolar with an average diameter of 29.7 mm as compared to the 1 to 25 mm distant subgroup with an average diameter of 19.4 mm. Mukicentricity. The overall frequency of multicentric foci of carcinoma among the 149 mastectomies was 20.8 per cent (31 cases). Multicentricity was defined as previously [4]. The frequency of multicentricity among cases of nipple involvement of any type, 28.8 per cent (13 of 45), was higher than that among cases of benign nipples, 17.3 per cent (18 of 104), but these differences were not significant by chi square analysis (Table VII).
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Clinical Recognition of Nipple Involvement. Twelve of 45 carcinomatous nipples were recognized as clinically abnormal (26.6 per cent). In 11 cases the nipple was fixed, indurated, or both, and in these infiltrating carcinoma was identified in the nipple stroma. The tumor lay directly under the nipple in nine, and in the two remaining cases the nearest radiographic tumor borders were 15 and 16 mm distant. A single case with a crusted nipple surface represented Paget’s disease (Table VIII). In summary, clinical inspection of the nipple identified an abnormality consistent with invasive involvement in half the invasive nipples. The remaining half of the invasive nipples were without clinically described abnormality but had a similar distribution of carcinoma. The latter were located beneath the nipple in seven cases, and in single instances at 5,10,25, and 35 mm distant. Clinical recognition of noninvasive carcinoma was poor; only 1 of 23 cases was identified as abnormal (4.3 per cent). This single case represented Paget’s disease of the nipple but was the only one of seven cases of Paget’s disease so recognized. Comments Three factors amenable to clinical evaluation are associated with a high frequency of nipple involvement by biologically more significant invasive carcinoma and appear useful in estimating the likelihood of nipple involvement. 1. Proximity of the tumor mass: In this study 95 per cent of all invasive nipples were associated with tumors that lay within 25 mm of the nipple margin, with a single exception at 35 mm. As noted previously [5-71, most of these tumors lay directly under the nipple or had a radiographic tumor border that extended to it, although 23 per cent of all cases of invasive nipple involvement were associated with more distant tumors. Proximity of the tumor to the nipple border appears to be the most reliable factor in predicting involvement by invasive cancer. 2. Tumor size: Involvement of the nipple by invasive carcinoma was significantly associated with
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Nipple
TABLE
IX
involvement
in Breast
Cancer
Comparative Relative Frequencies and Types of Nipple Involvement (per cent) Fisher et al (1975)
Invasive Infiltrating Lymphatic Noninvasive Paget’s or pagetoid In situ Total Overall frequency of carcinomatous nipple (per cent) Frequency of invasive nipple involvement
52.0 526 47.6 11.0 36.4 100 11.1 (107/967)
5.8
the maximum diameter of the invasive tumor mass. The average diameter of tumors associated with invasive nipples was 35 mm compared to an average of 19 mm for tumors associated with either noninvasive or benign nipples. Seventy-three per cent of all cases of invasive nipple involvement were associated with tumors greater than 2 cm in diameter (Table VI). This frequency is significantly different from that for noninvasive and benign nipple associated cancers (p = 0.01 and 0.1, respectively). S. Clinical nipple abnormality: In contrast to the foregoing factors, clinically recognizable changes suspicious of invasive involvement of the nipple, induration, fixation, and peau d’orange were present in only half the invasive nipples, despite a similar distribution of lesions within the breast among those with and without clinical abnormality of the nipple. This rather large unassessed carcinomatous involvement more closely parallels the data of Smith et al [6], in which only 31 of 66 nipples showed a clinical abnormality, than of Parry et al [ 71, in which 14 of 16 were abnormal. It should be emphasized, however, that although only half the nipples were recognized as abnormal, all those that were so recognized contained invasive cancer. A fourth factor amenable to preevaluation in a two-stage biopsy procedure is the degree of differentiation of the tumor. As noted previously [6,7], poorly differentiated ductal carcinomas are more frequently associated with invasive nipple involvement. In this study 68 per cent of all invasive nipples contained poorly differentiated ductal carcinoma, nearly twice the overall frequency of this tumor type in the series. Significantly, this was the only tumor type associated with invasive nipples in those cases in which the primary tumor was not directly beneath the nipple: the five invasive nipples between 1 and 25 mm and the single case at 35 mm were all associated with poorly differentiated ductal carcinoma.
Volume 139,July 1979
Smith et al (1976)
100
68.1 54.5 13.6 31.9 15.2 16.7
Excluded 100
100 12.2 (66/541)
a.3
Parry et al (1977)
8 (161200)
100
Present Studv 48.8 46.6 2.2 51.1 26.6 24.4 100 30.2 (451149)
14.7
The 30 per cent relative frequency of nipple involvement documented in this study is substantially greater than the range of 8 to 12 per cent noted previously. This represents both invasive and noninvasive involvement in a ratio similar to that noted in previous studies [5,6] (Table IX), but the present 14.6 per cent frequency of invasive involvement is nearly twice that of Smith et al [6]. This higher frequency probably reflects the more directed and extensive sampling of the nipple-areola complex incident to the Egan serial subgross technique. Most of the noninvasive nipple involvement was represented by microscopic, subclinical Paget’s disease and associated changes in lactiferous ducts. The significance of these incidental microscopic lesions in the nipple remaining after subcutaneous mastectomy or breast reconstruction has not been assessed prospectively. Such noninvasive lesions showed no substantial differences in frequency related to the proximity of the carcinoma to the nipple nor are they likely to be recognized clinically. However, the location of these noninvasive lesions was such that virtually all of them would have been excluded from the nipple after excision of a central core of nipple stroma and skin as part of a nipple-areola skeletonization procedure. Two recent case reports document the problems inherent in nipple transplantation. One report [8] describes the case of a nipple graft in the groin which was removed when the patient elected not to undergo breast reconstruction. Examination of the removed nipple revealed infiltrating lobular carcinoma. The primary tumor in this case measured 5 to 6 cm in diameter and was associated with two lymph node metastases, and carcinoma was present in sections taken from beneath the nipple. From the data we generated in the present study, breast reconstruction with nipple preservation would not have been considered for this patient. A second report [9] described
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Lagios et al
inguinal lymph node metastases of a poorly differentiated ductal carcinoma which developed after autotransplantation of a free nipple graft to the groin. The primary carcinoma in this case is described as a multifocal infiltrating ductal carcinoma with lymphatic invasion and lymph node metastases. Although the size and proximity of the tumor to the nipple cannot be ascertained, intraductal carcinoma was noted in the nipple bed not far from the cut surface. This case cannot clearly be evaluated in terms of the recommendations developed from the present study although the poorly differentiated histologic aspects of the inguinal metastasis, the multifocal infiltrating pattern of the primary tumor, and its lymphatic and axillary lymph node involvement suggest that this patient would not have fallen into the group for which breast reconstruction and nipple preservation would have been considered. Although the likelihood of invasive cancer in a nipple can be estimated with some confidence, noninvasive cancer within the nipple, albeit of unknown portent, cannot be similarly estimated from the data presently available. Summary Based on a serial subgross and correlated radiographic examination technique, the frequency of carcinomatous involvement of the nipple was found to be 30.2 per cent in a consecutive series of 149 mastectomy specimens. This is significantly higher than that in other reported series. Carcinomatous nipple changes in this series were equally divided between invasive and noninvasive types. The most common type of noninvasive cancer found was subclinical, microscopic pagetoid involvement of a lactiferous duct and associated microscopic Paget’s disease of the skin of the nipple. Of the nipples with invasive carcinoma, 95.4 per cent were associated with primary tumors less than 25 mm from the nipple. Invasive nipples were more likely to be associated with primary tumors that were poorly differentiated, greater than 20 mm in diameter, and contained axillary metastases than were benign or noninvasive nipples. Fifty per cent of nipples with invasive changes had macroscopic clinical abnormalities. There appeared to be no way to predict the presence of noninvasive carcinomatous involvement of a nipple other than by thorough direct sampling. The associated primary tumor locations were evenly distributed, and only 4.3 per cent of nipples involved with noninvasive cancer were clinically evident.
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However, removal of the nipple per se and skeletonization of the remaining areola would virtually eliminate the chance of residual noninvasive carcinoma. The higher incidence of nipple-areolar involvement in breast carcinoma found in this series compared to previous reports probably reflects the sampling technique. These data should be considered when approaching the problem of mastectomy and potential reconstruction for carcinoma of the breast. They are not to be interpreted to mean that the investigators are advocates of the procedure. References 1. Millard DR Jr, Devine J Jr, Warren WD: Breast reconstructions: a plea for saving the uninvolved nipple. Am J Surg 122: 763, 1971. 2. Millard DR Jr: Nipple and areola reconstruction by split-skin graft from the normal side. Plasf Reconsfr Surg 50: 350, 1972. 3. Egan RL, Ellis JT, Powell RW: Team approach to the study of diseases of the breast. dncer 23: 847, 1969. 4. Lagios MD: Multicentricity of breast carcinoma demonstrated by routine correlated serial subgross and radiographic examination. Cancer 40: 1726, 1977. 5. Fisher ER, Gregorio RM, Fisher B: The pathology of invasive breast cancer. A syllabus derived from findings of the National Surgical Adjuvant Breast Project (Protocol No. 4). Cancer 36: 1, 1975. 6. Smith J, Payne WS, Carney JA: Involvement of the nipple and areola in carcinoma of the breast. Surg Gynec Obsfet 143: 546, 1976. 7. Parry RG, Cochran TC Jr, Wolfort FG: When is there nipple involvement in carcinoma of the breast. Plast Reconsfr Surg 59: 535, 1977. 8. Allison AB, Howorth MB Jr: Carcinoma in a nipple preserved by heterotopic auto-implantation. N Engl J Med 298: 1132, 1978. 9. Bouvier B: Problems in breast reconstruction. MedJ Aust 1: 937, 1977.
Discussion John M. Goin (Los Angeles, CA): This exceptionally important work has many implications, particularly in breast reconstruction after mastectomy. One earlier report of 200 breasts showed that only 8 per cent had microscopic evidence of cancer in the nipple, and of these 16 nipples, only 2 looked grossly normal. The present paper, reflecting a closer and more sophisticated scrutiny, shows that only half the nipples containing invasive carcinoma could be recognized clinically. One of the major implications of this work is that if there is a significant chance of transmitting cancer by nipple banking, the procedure has to be abandoned. There are two reports of transplantation of cancer to the groin via a banked nipple. Careful study of these reports shows that carcinoma was present in or not far from the sections taken from beneath the removed nipple. In one case the cancerous lesion was very large, 5 to 6 cm in size. In the other report, tumor size was not mentioned.
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Nipple Involvement
It seems clear, however, from the scanty information available that neither nipple should have been preserved. The data just presented suggests that nipples can be banked with considerable confidence when the nipple is normal in appearance and the primary tumor is well differentiated, smaller than 1.9 cm, and located more than 3.5 cm from the nipple margin. I would add to these criteria negative frozen section examination of both the subareolar breast tissue and a core from the interior of the nipple itself. Smith, Paine, and Carney in a similar study also concluded that when the nipple-areolar complex is clinically normal and the tumor is smaller than 2 cm and not situated behind the nipple, nipple involvement by carcinoma is rare. Virtually all$f the noninvasive nipple lesions could have been avoided by transplantation of only the areola, although the subsequent importance of these microscopic changes in the clinical course of the patient is not entirely clear. The use of an areolar graft alone does not seriously compromise the quality of reconstruction since nipple protrusion in an areolar graft can be simulated with implanted disks of auricular cartilage or composite ear lobe graft.s. For the truly fastidious, even the tubercles of Montgomery can be mimicked by tiny cartilage grafts scattered beneath the areolar graft. Ironically, as the bases for nipple banking have become more scientific, enthusiasm for the procedure has somewhat waned. Any free graft, including a banked nipple, that is transferred twice develops fibrosis and pigmentary changes that lead to a less than elegant result. Consequently, a number of new and ingenious methods of nipple reconstruction have been developed that some plastic surgeons believe have reduced the need for nipple banking. Pigmented skin from the upper thigh and perineum has also been used as well as retroauricular skin. Tom Cronin, an ingenious plastic surgeon from Houston, has even reconstructed nipples with hemorrhoids. The real problem is making two nipples that look alike. Nipple banking probably comes closer to this goal than any other method when only one breast is operated on. When it is necessary to operate on the other breast as well, whether to remove it for premalignant disease or to alter it for symmetry, satisfactory bilateral nipple reconstruction can almost always he accomplished by sharing the remaining nipple-areolar complex between the two breasts. Leon Morgenstern (Los Angeles, CA): In 1975 I reported to this Association a study on the multicentricity of breast carcinoma based on a review of 500 consecutive cases. Part of that study related to nipple involvement as a type of multicentricity. Nipple involvement occurred in 12.5 per cent of our multicentric lesions, or 5 per cent of the total series. We excluded all cases in which primary tumors
Volume
138,July
1979
in Breast Cancer
were contiguous with the nipple, and all our cases of nipple involvement were unsuspected on clinical grounds. Moreover, most were associated with tumors more than 25 mm distant from the nipple. Whether the incidence of nipple involvement is 5 per cent, as reported in our series, 8 to 12 per cent as reported elsewhere, or the astounding 30.2 per cent described in this series, the basic question is the meaning of this finding relative to nipple salvage for reconstruction. I firmly believe that if there is even a remote chance of transplanting tumor cells, and all these studies not only strongly suggest hut also prove that possibility, then this is an unacceptable practice in tumor surgery. Already in 1978 one instance of carcinoma has been described in a nipple preserved by heterotopic autotransplantation. Anecdotal reports grow to become series. I have little doubt that the preserved nipple-areolar complex, however salvaged in patients with carcinoma, will eventually cause transplantation of tumor cells in some persons. “Virtual” elimination of this risk is not a reasonable way to deal with carcinoma. Donald L. Morton (Los Angeles, CA): This study points out the frequency of histologic involvement of the nipple. My conclusion is that nipple autotransplantation is a lot of gobbledygook. If you can find histologic evidence of cancer in 30 per cent of nipples, doesn’t that mean that biologic cancer is there more frequently? How many times have we performed cancer surgery and had the pathologist report negative margins only to have recurrence? Histopathologic involvement usually underestimates the biologic recurrence rate. Therefore, it is wrong to save a nipple that is potentially involved with cancer. The patient is coming to you for treatment of cancer of the breast. Your first obligation is to treat that cancer properly, and to put the patient at risk of autotransplantation of tumor cells to a distant site, as well as hack to the same site so that she may have a more normal appearing nipple, to me is ridiculous and I just cannot accept it. Perhaps I have been privileged by working with a very talented group of plastic surgeons, hut Drs. Zarem and Miller and the group at UCLA effect a very respectable nipple from vulvar skin, and, in fact, some of our patients do not bother to wear bras after reconstruction. Therefore, to employ a procedure that exposes a patient to the danger of implantation of cancer cells just does not make good surgical sense when there are alternatives. While I have the opportunity, I might ment,ion another mistake in the management of breast disease which we are seeing more frequently and which involves patients who have had so-called subcutaneous mastectomy as a cancer-preventing operation. We have had a number of these women in our clinic who present within 2 or 3 years with cancer of the breast after this subcutaneous operation. Unfortunately, subcutaneous mastectomy is not total mastectomy, and cancer of the breast may still develop. There is no good information on whether this procedure prevents breast cancer, and although this operation may
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theoretically be appealing, we really must be careful before proceeding with subcutaneous mastectomy as a cancer preventive until we have some evidence of its effectiveness. Philip R. Westdahl (closing): Our purpose in presenting this study was not to advocate this procedure. This study was undertaken to find an accurate means of determining when the nipple-areolar complex might be involved, hoping thereby to discourage the procedure when it obviously should never be considered in the first place. Dr. Goin referred to those patients. We also wished to determine when it might be considered safe for those patients who might have a compelling desire for breast reconstruction. Dr. Lagios is to be commended on the thoroughness of his project. I still consider myself a cancer surgeon, not a plastic
142
surgeon. However, patients have heard about this procedure and some of them ask about it. They want to know everything possible about what can be done for them before mastectomy is undertaken. This study has enabled me to be more factual in discussing breast reconstruction with such patients. I do not disagree at all with Drs. Morgenstern and Morton. I believe, as they do, that the primary purpose of a cancer operation is to remove the local disease, and that preserving the nipple is a secondary consideration. Dr. Goin has described additional sources for reconstruction of the nipple. This study may also help us to better evaluate the efficacy of subcutaneous mastectomy as a prophylactic procedure in advanced mammary dysplasia or in very high risk patients and as a therapeutic procedure in patients with microscopic foci of carcinoma in situ.
The American Journal of Surgery