Terminal Duct Lobular Units are Scarce in the Nipple: Implications for Prophylactic Nipple-Sparing Mastectomy

Article (PDF Available)inAnnals of Surgical Oncology 15(2):438-42 · March 2008with45 Reads
DOI: 10.1245/s10434-007-9568-4 · Source: PubMed
The use of nipple-sparing mastectomy (NSM) for both breast cancer treatment and risk reduction is increasing. There is no randomized data comparing nipple-sparing mastectomy with standard mastectomy techniques. There is evidence to suggest that ductal and lobular breast cancer arises in the terminal duct/lobular unit (TDLU). This study was undertaken to determine whether TDLUs exist in the nipple and if so, to what extent. At the time of mastectomy the nipple papilla was excised and submitted for separate pathological examination. The presence or absence of TDLUs was noted. Thirty-two nipples were studied in 22 patients. There were no TDLUs in 29 specimens. Three of 32 nipple specimens were found to contain TDLUs. The three nipples contain one, two, and three TDLUs respectively. All TDLUs were found at the base of the nipple, with none located near the tip. The infrequent occurrence of TDLUs in the nipple papilla supports the use of NSM for risk reduction surgery, including for those women with BRCA1/2 mutations.


Terminal Duct Lobular Units are Scarce in the Nipple:
Implications for Prophylactic Nipple-Sparing Mastectomy
Terminal Duct Lobular Units in the Nipple
Alan J. Stolier, MD FACS,
and Jianzhou Wang, MD
Tulane University Department of Surgery and Omega Hospital, 2525 Severn Ave, New Orleans, LA, USA
Department of Pathology, Ochsner Health System, New Orleans, LA, USA
Background: The use of nipple-sparing mastectomy (NSM) for both breast cancer treat-
ment and risk reduction is increasing. There is no randomized data comparing nipple-sparing
mastectomy with standard mastectomy techniques. There is evidence to suggest that ductal
and lobular breast cancer arises in the terminal duct/lobular unit (TDLU). This study was
undertaken to determine whether TDLUs exist in the nipple and if so, to what extent.
Methods: At the time of mastectomy the nipple papilla was excised and submitted for
separate pathological examination. The presence or absence of TDLUs was noted.
Results: Thirty-two nipples were studied in 22 patients. There were no TDLUs in 29
specimens. Three of 32 nipple specimens were found to contain TDLUs. The three nipples
contain one, two, and three TDLUs respectively. All TDLUs were found at the base of the
nipple, with none located near the tip.
Conclusions: The infrequent occurrence of TDLUs in the nipple papilla supports the use of
NSM for risk reduction surgery, including for those women with BRCA1/2 mutations.
Key Words:
Prophylactic mastectomy—BRCA1/2—Breast anatomy—Breast cancer.
As breast cancer tumor size has decreased during
recent decades, the extent of surgery for breast cancer
has shown similar reductions. Radical mastectomy
with routine skin grafting evolved from radical mas-
tectomy with primary skin closure, into modified
radical mastectomy, then into lumpectomy. However,
mastectomy is still being carried out for a variety of
indications including extensive cancer and prophy-
lactic mastectomy for risk reduction, as well as pa-
tient choice. As breast reconstruction, both with
synthetic implants and autologous tissue, entered the
mainstream, it was obvious that retention of the
breast skin envelope resulted in a superior cosmetic
result. Multiple nonrandomized series of skin-sparing
mastectomies (SSMs) have now been published
suggesting similar recurrence rates to those of mas-
tectomy done us ing the more classical mastectomy
The evolution continues, with the
appearance of several relatively small series of nipple-
sparing mastectomies (NSMs) undertaken both for
cancer and risk reduction.
The sequencing of the BRCA1 and BRCA2 genes
has allowed women, in many instances, to obtain an
accurate estimation of breast cancer risk. Many
women who test positive for a deleterious mutation
elect to undergo prophylactic mastectomy.
Whether nipple-sparing maste ctomy should be uti-
lized in these instances is unknown. Without pub-
lished randomized trial data, surgeons will depend
on surrogate information to make decisions as to
Received June 8, 2007; accepted July 17, 2007; published online:
November 14, 2007.
Address correspondence and reprint requests to: Alan J. Stolier,
MD FACS; E-mail: astolier@tulane.edu
Published by Springer Science+Business Media, LLC Ó 2008 The Society of
Surgical Oncology, Inc.
Annals of Surgical Oncology 15(2):438–442
DOI: 10.1245/s10434-007-9568-4
whether NSM is oncologically sound. Germane to
this subject is the anatomic origin of breast cancer
and to what extent this anatomy exists in the nipple.
This study was designed in an attempt to answer
these questions.
Following mastectomy, the nipple was grasped
with a straight-jawed non-crushing clamp and tran-
sected using a scalpel or straight scissors at the
junction of the nipple papilla and the areola (Fig. 1).
The nipples were serially sectioned vertically, using
2 mm thickness, and the sections were entirely sub-
mitted for routine haematoxylin and eosin (H and E)
microscopic examination for the presence or absence
of terminal duct lobular units (TDLUs).
Nipple anatomy was studied in 22 patients. Ten
patients had bilateral procedures, giving a total of 32
nipple specimens. The indications for surgery can be
seen in Table 1. Twenty-two mastectomies were
undertaken for prophylaxis, four for invasive ductal
carcinoma, four for ductal carcinoma in situ, and one
for invasive lobular carcinoma. Three patie nts
undergoing four mastectomies tested positive for a
BRCA1/2 gene mutation. Patient ages ranged from
37 to 76 with a mean age of 52.5 years.
Sections of nipples show skin and abundant inter-
lacing fascicles of smooth muscle fibers. The nipple
skin contains sebaceous glands and apocrine glands.
The dilated lactiferous sinuses and branching lactif-
erous ducts are seen. Three of 32 nipple specimens
(9%) were found to contain TDLUs. The three nip-
ples contained one, two, and three TDLUs respec-
tively. No TDLUs were identified in the remaining 29
specimens. All TDLUs were located at the base of
nipples. No evidence of atypical ductal hyperplasia,
ductal carcinoma in situ, or invasive ductal carcinoma
was identified in any of the 32 nipple specimens.
Occult nipple involvement in underlying cancer has
been described. Anat omic and pathologic features
increasing the risk of nipple involvement have also
been noted.
Guidelines, however, do not exist
when considering NSM in the risk reduction or pro-
phylactic setting. It is in this setting that knowledge
of the anatomic origin of breast cancer may be
helpful in determining the risk of subsequent new
breast cancers. Much of the work on the anatomic
origin of breast cancer was carried out by Wellings,
Jensen, and associates.
Utilizing whole-mount
methodology, and subgross microscopic examination
, they evaluated 196 breasts, 119 of which were suit-
able of quantitative morphologic study. They con-
cluded that ‘‘the basic reacting unit in practically all
dysplastic, metaplastic, hyperplastic, anaplastic and
neoplastic lesions of the human breast is the terminal
ductal-lobular unit.’’ The only exceptions they cite
are intraductal papillomas and rarely occurring epi-
thelial hyperplasia arising in larger ducts. In 1959
Parks also concluded that breast cancer arises in the
Although the existing evidence is not en-
tirely conclusive, it seems reasonable to conclude that
both ductal and lobular carcinoma share a common
origin in the TDLU.
Are TDLUs found in the nipple? Clearly, the an-
swer to this question is important when considering
the use of NSM performed for risk reduction. In a
very detailed histologic study of the nipple by
Montagna there is an extensive discussion of the
lactiferous ducts and sebaceous gland structures in
the nipple with no mention of TDLU.
Similarly, in
histological studies by Going and Moffat,
Love and
and Taneri et al.
focus almost exclusively
on the anatomy of the lactiferous system and the
number of ducts emptying onto the nipple. Again
there is no mention of TDLUs in the nipple. Only one
study, by Rosen and Tench, addressed the presence of
TDLU in the nipple.
They found that TDLUs ex-
isted in only 17 of 101 cases studied. In five cases
FIG. 1. The nipple is transected at the base of the nipple papilla.
TABLE 1 Indications for surgery
Indications for surgery Number (%)
Prophylactic 22 (69)
Invasive ductal carcinoma 4 (12)
Invasive lobular carcinoma 1 (3)
Ductal carcinoma in situ 5 (16)
Total 32
Ann. Surg. Oncol. Vol. 15, No. 2, 2008
where no TDLUs were found, the nipples were sec-
tioned more extensively and reexamined. No TDLUs
were found in these five cases leading them to con-
clude that ‘‘lobules are absent from some nipples.’’
Most importantly, Rosen and Tench defined the
nipple in histological terms as being represented by
the presence of lactiferous ducts. In our study, we
defined the nipple in surgical terms; being the actual
papilla that is elevated above the level of the sur-
rounding areola. This distinction is of more than just
passing interest. In considering NSM, the surgical
anatomy is more meaningful than the histologic
anatomy. It is the elevated portion of the nipple, the
papilla, which is spared, with tissue deep to the pa-
pilla being removed. Moreover, it seems clear from
the work of Going and Moffat that the lactiferous
ducts extend below the nipple papilla (Fig. 2). In our
study we found that 91% (29 of 32) of nipples studied
contained no TDLUs. In the three cases where
TDLUs were identified, their distribution was sparse.
Without TDLUs, the nipple would be an unusual
site to develop a primary cancer. A review of the
pathologic studies from the National surgical adju-
vant breast project (NSABP) B-04
and B-06,
well as a search of the literature, failed to yield a
single mention of primary breast cancers originating
in the nipple. Even in patients with BRCA1/2 muta-
tions, it is likely that NSM might still yield results
comparable to the 90–95% risk reduction that is
currently reported.
The distinction between our own work and that of
Rosen and Tench is also important when considering
whether surgeons should attempt to remove tissue
from within the nipple papilla. How thoroughly duc-
tal tissue is removed from the nipple using current
techniques is not known. The earliest mention of the
term ‘‘coring’’ appears to be by Randall et al. in
They referred to the process as ‘‘apple coring’’
and described a method by which the entire tip of the
nipple is removed with nipple contents, thereby
assuring removal of all ducts. Our current approach ,
as well as that of others,
is much less radical and does
not include removal of the tip of the nipple. It would
seem reasonable to conclude that the low prevalence
of TDLUs in the nipple papilla might obviate the need
to radically remove nipple contents. In this c urrent
study we also observed that when TDLUs were
present, they wer e universally located near the base of
the nipple, with no TDLUs found at the tip. Therefore
we woul d also suggest that removal of tissue from the
nipple be limited to the region near its base.
What is the risk of PagetÕs disease of the nipple in
patients undergoing prophylactic NSM? A literature
search fails to reveal any studies examining this spe-
cific problem. The great preponderance of cases are
associated with underlying breast carcinoma. In one
of the largest series of PagetÕs disease, Ashikara et al.
studied 214 cases and found that only 2.8% of cases
not to have an associated breast cancer.
In a study
from Guy Õs Hospital, 35 consecutive patients under-
going mastectomy for PagetÕs disease were found to
have either invasive ductal carcinoma or ductal car-
cinoma in situ.
Further supporting the connection
between Pag etÕs and underlying breast cancers are
studies using immunohist ochemistry to characterize
and compare the nipple disease and the underlying
Though one must consider the possibility of
FIG. 2. Digital model of nipple duct anatomy. Note the extension
of the lactiferous ducts below the base of the nipple. From Going
JJ, Moffat DF.
Reproduced with permission by John Wiley &
Sons Ltd on behalf of PathSoc.
Ann. Surg. Oncol. Vol. 15, No. 2, 2008
pagetoid spread of cancer to the nipple when per-
forming NSM for cancer, it seems unlikely that Pa-
getÕs disease originating in the nipple would
significantly affect risk of future breast cancer.
One might consider cancers arising in papillomas
as an exception to the origin of cancers in the TDLU.
Two types of papillomas have been described. One,
termed ‘‘peripheral,’’ arises from the TDLU. The
other type is ‘‘central’’ and arises in the large central
Page et al. reported a relative risk of
developing cancer in a papilloma of 7.5 when atypia
is present.
Since most papillomas are asymptom-
atic, the actual risk of cancerous transformation is
difficult to ascertain. The risk of malignant trans-
formation of a papillary lesion has been shown to be
higher in peripheral lesions compared to central. In
the pathological review of cases from NSABP B-04
(Radical mastectomy versus simple mastectomy ver-
sus simple mastectomy plus radiation), Fisher et al.
noted that only 0.4% of cases had pure papillary
Again, without reports of primary breast
cancer arising in the nipple the actual incidence is
unknown. One might reason, however, that this risk
is exceptionally low.
It is likely that the number of mastectomies per-
formed for risk reduction is rising. The advent of
genetic testing, the good results demonstrated in risk
reduction studies and the improvements in breast
reconstruction techniques are likely to be responsible.
It is also likely that most breast cancers arise from the
TDLU. The infrequent occurrence of TDLUs in the
nipple papilla would therefore make the developm ent
of a primary cancer in this area unusual. Although
this study does lend support to the use of NSM for
risk reduction surger y, including in those women with
BRCA1/2 mutations, only prospective studies can
accurately define its indications and safety.
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    • "It is assumed that ductal and lobular breast cancer arises in the terminal duct/lobular unit (TDLU), and that from these putative remaining ducts there may originate a certain risk of recurrence or even new breast cancer. Stolier et al. [29] investigated the existence and the extent of TDLU in the nipple in 32 mastectomy specimens. TDLU were found in only three nipples at the base, with none located in the tip. "
    [Show abstract] [Hide abstract] ABSTRACT: Skin-sparing (SSM) and nipple-sparing mastectomy (NSM) have gained widespread popularity over the past few years. Breast reconstruction is facilitated and the aesthetic result is improved in comparison to patients undergoing mastectomy alone. The oncologic safety has been demonstrated in various publications. However, discussions still arise regarding correct patient selection and the role of histologic assessment of the subareolar tissue of the nipple areola complex (NAC) to exclude possible tumor infiltration, as this is the main limiting factor of NSM. This review focuses on oncologic consideration, correct patient selection, and surgical management for patients eligible for SSM/NSM. The most recent literature was reviewed to provide evidenced-based recommendations for daily clinical routine.
    Full-text · Article · Jun 2011
    • ". Voraussetzungen für eine NSM sind eine Tumorgröße unter 5 cm, ein Abstand von mindestens 2 cm zwischen Tumor und Mamille sowie ein negativer intraoperativer Gefrierschnitt des intramamillären Gewebezylinders (¼ Coring) [4]. Bei Einhalten dieser Standards ist von einer Lokalrezidivrate im Bereich des Nippel-Areola-Komplexes (NAC) von weniger als 2 % und bei prophylaktischer NSM von einer de-novo Krebsentstehung im NAC von unter 1 % auszugehen [5] [6]. "
    [Show abstract] [Hide abstract] ABSTRACT: Die operative Therapie des Mammakarzinoms spielt trotz der raschen Weiterentwicklung der systemischen Therapie noch immer eine zentrale Rolle. Bei mehr als zwei Drittel aller Patientinnen kann brusterhaltend operiert werden, wobei neben der onkologischen Sicherheit auch das resultierende kosmetische Ergebnis eine wichtige Rolle für die Patientinnen spielt. Daher ist es für Brustoperateure unumgänglich, sich mit den verschiedenen Methoden der Onkoplastik auseinanderzusetzen. Falls eine Mastektomie erforderlich ist, sollte das rekonstruktive Element von Anfang an angeboten und miteingeplant werden, da in vielen Fällen hautsparende Methoden und Sofortrekonstruktionen möglich sind. Although systemic treatment strategies are improving continuously, breast surgery still plays a central role in the management of breast cancer. Because breast conserving therapy is feasible in more than two thirds of breast cancer patients, breast surgeons should be aware of the different oncoplastic techniques. The development of skin sparing techniques combined with immediate reconstruction provides good cosmetic results in many cases in which mastectomy is required. Therefore the reconstructive element should be offered and integrated in the therapy plan as soon as mastectomy is indicated. SchlüsselwörterMammakarzinom-Operative Therapie-Onkoplastik-Rekonstruktion KeywordsBreast cancer-Breast surgery-Breast reconstruction
    Article · Nov 2010
    • "They also reviewed some of the literature on terminal ductal lobular units in the nipple. The incidence was reported to be between 9% and 17%, with most of the terminal ductal lobular units at the base of the nipple papilla.26 They cautioned against fixed-volume reconstructions after NSM because of a higher incidence of NAC necrosis. "
    [Show abstract] [Hide abstract] ABSTRACT: The use of areola-sparing (AS) or nipple-areola-sparing (NAS) mastectomy for the treatment or risk reduction of breast cancer has been the subject of increasing dialogue in the surgical literature over the past decade. We report the initial experience of a large community hospital with AS and NAS mastectomies for both breast cancer treatment and risk reduction. A retrospective chart review was performed of patients undergoing either AS or NAS mastectomies from November 2004 through September 2009. Data collected included patient sex, age, family history, cancer type and stage, operative surgical details, complications, adjuvant therapies, and follow-up. Forty-three patients underwent 60 AS and NAS mastectomies. Forty-two patients were female and one was male. The average age was 48.7 years (range, 28-76 years). Forty mastectomies were for breast cancer treatment, and 20 were prophylactic mastectomies. The types of cancers treated were as follows: invasive ductal (n = 19), invasive lobular (n = 5), ductal carcinoma-in situ (n = 15), and malignant phyllodes (n = 1). Forty-seven mastectomies (78.3%) were performed by inframammary incisions. All patients underwent immediate reconstruction with either tissue expanders or permanent implants. There was a 5.0% incidence of full-thickness skin, areola, or nipple tissue loss. The average follow-up of the series was 18.5 months (range, 6-62 months). One patient developed Paget's disease of the areola 34 months after an AS mastectomy (recurrence rate, 2.3%). There were no other instances of local recurrence. AS and NAS mastectomies can be safely performed in the community hospital setting with low complication rates and good short-term results.
    Article · Oct 2010
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