Mammaglobin immunostaining in the differential diagnosis between cutaneous apocrine carcinoma and cutaneous metastasis from breast carcinoma.
ABSTRACT The differential diagnosis between cutaneous apocrine carcinoma (CAC) and cutaneous metastases from breast carcinoma is commonly difficult. Many times, clinical information is crucial in the final diagnosis, because help that can be obtained from immunohistochemistry is usually limited concerning this subject. We used the antibody mammaglobin in order to study 10 cases of cutaneous metastasis of ductal breast carcinoma, and 2 cases of CAC. One of the CAC cases showed only scattered positive cells, while the other did not show any positivity. Four cases of metastatic breast carcinoma also showed scattered positive cells. In other five metastatic cases, positive cells were abundant, representing up to 60% of the tumoral cells. One case of metastatic breast carcinoma did not show any expression of mammaglobin at all. Although, more cases of CAC should probably be studied in the future before any categorical conclusion can be obtained, our results seem to indicate that a pattern of immunostaining with expression of mammaglobin in many cells would favor a metastatic origin of the tumor.
Article: Contrary view: the breast is not an organ per se, but a distinctive region of skin and subcutaneous tissue.American Journal of Dermatopathology 05/2007; 29(2):211-8. · 1.20 Impact Factor
Article: The breast is not an organ.The American Journal of dermatopathology 07/2008; 30(3):304. · 1.30 Impact Factor
Article: An immunohistochemical study of lysozyme, CD-15 (Leu M1), and gross cystic disease fluid protein-15 in various skin tumors. Assessment of the specificity and sensitivity of markers of apocrine differentiation.[show abstract] [hide abstract]
ABSTRACT: We investigated immunohistochemically the localization of lysozyme and Leu M1 in normal skin, 76 cases of benign sweat gland tumors, 28 cases of malignant sweat gland tumors, 23 cases of extramammary Paget's disease, 7 cases of sebaceous carcinoma, 6 cases of malignant trichilemmoma, 10 cases of squamous cell carcinoma, and 10 cases of basal cell carcinoma and compared the results with those for gross cystic disease fluid protein (GCDFP)-15 to assess the sensitivity and specificity of our assay conditions for apocrine differentiation. Normal apocrine glands were stained with all three antibodies, while eccrine glands were positive only for GCDFP-15, and other portions of normal skin were not stained with any of the antibodies used. In neoplastic tissue thought to be from apocrine tumors, antibodies raised against lysozyme and GCDFP-15 had a greater specificity (100%) for apocrine differentiation, while Leu M1 had a greater sensitivity (88%). Tissues that were stained with two or three of these antibodies appeared to exhibit apocrine differentiation. In the tumors examined, the specificity for apocrine differentiation was 100% and the sensitivity for such differentiation was 92% by these criteria. According to these criteria, some cases of syringocystadenoma papilliferum, primary mucinous carcinoma of the skin, and extramammary Paget's disease with underlying adenocarcinoma showed apocrine differentiation.American Journal of Dermatopathology 07/1995; 17(3):249-55. · 1.20 Impact Factor
Cutaneous apocrine carcinoma (CAC) is an elusive
malignancy among the adnexal tumors. On the contrary to
other adnexal tumors, the differential diagnosis with a
cutaneous metastasis from a breast carcinoma is extremely
difficult, up to the point that many reports emphasize how
crucial the clinical information is. The immunohistochemistry
has not been of much help in order to discriminate between
both conditions. Many of these thoughts are presented in a
recent article by Adámková et al. (3).
Mammaglobin is a relatively new antibody that intensively
stains ductal breast carcinomas. Although the staining pattern
with mammaglobin has been investigated in certain benign
apocrine tumors, its expression has not been checked in
In this report, we investigated the expression of
mammaglobin by two CACs, as well as by 10 cutaneous
metastases from ductal breast carcinoma, in order to check if
mammaglobin might help in the differential diagnosis between
MATERIAL AND METHODS
The cases were recovered from our archives, revising the
We performed an immunohistochemical study in all the
cases, with the monoclonal mouse anti-human mammaglobin
antibody of DakoCytomation (Clone 304-1A5; code N1637),
and with the Dako REAL EnVision detection system.
The details about the selected cases, including location of
the tumors and gender and age of the patients are shown in
One of the CACs showed a common tubular morphology
(Fig.1; bottom), while the second had a cribriform pattern (Fig.
1; top). This latter case has been reported on its own before (13).
The differential diagnosis between cutaneous apocrine carcinoma (CAC) and cutaneous metastases from breast carcinoma is commonly
difficult. Many times, clinical information is crucial in the final diagnosis, because help that can be obtained from immunohistochemistry is
usually limited concerning this subject.
We used the antibody mammaglobin in order to study 10 cases of cutaneous metastasis of ductal breast carcinoma, and 2 cases of
CAC. One of the CAC cases showed only scattered positive cells, while the other did not show any positivity. Four cases of
metastatic breast carcinoma also showed scattered positive cells. In other five metastatic cases, positive cells were abundant,
representing up to 60% of the tumoral cells. One case of metastatic breast carcinoma did not show any expression of mammaglobin
at all. Although, more cases of CAC should probably be studied in the future before any categorical conclusion can be obtained, our
results seem to indicate that a pattern of immunostaining with expression of mammaglobin in many cells would favor a metastatic
origin of the tumor.
Key words: mammaglobin – apocrine gland carcinoma – metastatic carcinoma – ductal carcinoma – breast
Imunohistologický průkaz mamaglobinu v diferenciální diagnostice mezi apokrinním karcinomem kůže
a kožní metastázou karcinomu prsu
Diferenciální diagnóza mezi apokrinním karcinomem kůže (AKK) a kožní metastázou karcinomu prsu je často obtížná. Spíše než
imunohistologie může pomoci klinická informace.
Použili jsme protilátku mamaglobin k vyšetření 10 případů kožní metastázy duktálního karcinomu prsu a 2 případů AKK. V jednom
z případů AKK byly pozitivní jen ojedinělé buňky, druhý případ byl negativní. Z 10 případů metastázy karcinomu prsu byly v 5 pozitivní
buňky četné (až 60 % nádorových buněk), ve 4 byly pozitivní ojedinělé buňky a 1 případ byl negativní.
Jsme si vědomi, že by bylo v budoucnu vhodné vyšetřit více případů AKK než bude možno vyslovit kategorický závěr; naše výsledky
však ukazují, že imunohistologický průkaz exprese mamaglobinu v četných buňkách nádoru může svědčit pro jeho metastatický
Klíčová slova: mamaglobin – karcinom apokrinní žlázky – metastatický karcinom – duktální karcinom – prs
Čes.-slov. Patol., 45, 2009, No. 4, p. 108–112
MAMMAGLOBIN IMMUNOSTAINING IN THE DIFFERENTIAL DIAGNOSIS
BETWEEN CUTANEOUS APOCRINE CARCINOMA AND CUTANEOUS
METASTASIS FROM BREAST CARCINOMA
Service of Cellular Pathology, Clinica Ponferrada, Ponferrada, Spain
In the immunohistochemical study, one of the cases of CAC
(case number 2) showed only scattered positive cells
(Fig.2.A), while the other did not show any positivity. Four
cases of metastatic breast carcinoma showed a similar pattern
of immunostain like the one observed in case number 2, with
scattered cells expressing the antigen (Fig 2.B). In other five
metastatic cases, positive cells were abundant and
represented up to 60% of the tumoral cells (Fig.3). One case
of meatastatic breast carcinoma did not show any expression
Our results lead us to conclude that a pattern of
immunostaining with many positive cells for mammaglobin
would favor a metastasis from breast duct carcinoma. With
“many”, we mean a pattern of expression in which more than
only scattered cells are stained. Although the definition might
sound ambiguous, a posititivity of more than 10% of the
tumoral cells sounds as a reasonable condition. On the
contrary, a pattern of immunostaining with “few scattered
positive cells only” would not favor any of the two possibilities,
and the same would happen if there was no expression of the
marker. With the limited number of CAC cases that we studied,
one should be cautious before such conclusions can be
categorized and more studies with the antibody would be
necessary in the future.
Another limitation of our study is that all cases studied from
breast were ductal carcinomas instead of the specific apocrine
carcinoma of breast. Althought breast is considered by many
as a modified apocrine gland (1, 2), it could be claimed that
perhaps the expression of apocrine carcinomas of the breast
would have been different. Nevertheless, some studies on the
subject have demonstrated that “breast tumoral cells with both
Fig. 1. The two cases of CAC showed a cribriform (top) and
tubuliform (bottom) pattern, respectively.
Fig. 2. A) Scattered positive cells for mammaglobin in one of the
CAC cases (number 2)
B) A similar pattern was observed in four cases of metastatic
carcinoma from the breast.
Fig. 3. Abundant positive cells expressing mammaglobin were
observed in five of the metastatic cases.
apocrine and non-apocrine features express mammaglobin
with roughly equal frequency and intensity” (39).
The information obtained gives us some help from the field
of immunohistochemistry in a subject which is always difficult:
the main differential diagnosis when facing a cutaneous
apocrine carcinoma (CAC) is a metastasis from a breast
carcinoma or also a carcinoma that arises in an axillary breast
prolongation (17) or in ectopic mammary tissue (7, 20, 26, 35,
Some morphologic clues have been mentioned in literature
in order to distinguish between both entities (32, 35), and one
of the most helpful ones is the evidence of an in situ sweat
gland component, which points out towards a CAC (9, 39).
Since that finding is far from being the rule, the differential
diagnosis between a primary tumor and a metastasis can
sometimes be impossible without the appropriate clinical
information (7, 20, 26, 35, 37, 39).
The immunophenotype of the tumor is only of a relative
help in distinguishing its origin. In the past, some authors
pointed out that an intense immunolabelling for CEA,
especially in the absence of expression of GCDFP-15 by
tumoral cells, would favour a primary cutaneous CAC over a
metastasis from a breast carcinoma (20, 39). In fact, many
of the CACs reported have shown a weak and focal
expression of GCDFP-15 (26), or have failed to show any
expression at all of the marker (7, 23, 24, 40). This is in spite
of the fact that GCDFP-15 is considered as a very specific
marker for apocrine differentiation (23, 39).
in a series, GCDFP-15 failed to mark four ductal breast
carcinomas, while it was expressed by the only CAC studied
(4), therefore demonstrating the relative use of the marker in
this specific differential. Others demonstrated GCDFP-15 in
less than half of their cases of breast carcinoma skin
It was sometime suggested that an immunophenotype
androgen receptor (AR)+, estrogen receptor (ER)-,
progesterone receptor (PR)-, would favour an apocrine origin
(11, 25), since it is expressed not only by normal apocrine
glands (11), but also by apocrine carcinomas (11, 22, 34) and
by extrammary Paget disease, which is alleged by some to
origin from apocrine glands (11). This latter point is
nevertheless highly controversial, since the discovery of Toker
cells also in the vulva (42). These cells are claimed as the
precursor of extrammamary Paget disease by some (5, 15).
An immunophenotype ER- PR- AR+ has not been the rule in
all CACs studied in literature. Some for instance have
demonstrated expression of ER in cribriform CAC (13). Some
others have demonstrated expression of PR by apocrine
adenomas, as well as by papillary CACs (23). Recently,
Robson et al. studied a large series of CACs and
demonstrated that 62 % were ER+, 60 % were PR+ and 36 %
were AR- (30).
Cytokeratin (CK) 7 has been demonstrated as a good
marker for Toker cells (14, 21, 41, 42) as well as for Paget
disease, either mammary (26), or extrammary. It has not been
found as useful in the diagnosis between a primary adnexal
tumor and a metastasis, unless used as a part of an antibody
panel (29). It is interesting how the pattern of immunostaining
is important: focal CK7 expression was suggestive of a primary
adnexal tumor, while diffuse immunostaining was mainly seen
in a metastasis (29). This is similar to our results with
mammaglobin, with a focal pattern favouring a primary tumor.
This rule regarding CK7, nevertheless, seems to faint when
distinguishing between CAC and a cutaneous metastasis of a
breast carcinoma. CK7 has been demonstrated strongly and
diffusely expressed by primary CAC (13).
Recently, p63 has been found to be of much use in the
differential diagnosis of primary adnexal tumors versus
metastatic adenocarcinomas to the skin (18, 19, 28).
However, CAC has been proved to be an exception, since
not only its metastases but also the primary tumor does not
express any p63 (19).
Other markers which are sometimes mentioned in the
literature, in the diagnosis of primary cutaneous adnexal
tumors, are only of relative help when facing a possible CAC.
Cytokeratin (CK) 5/6, for instance, is usually expressed
strongly and diffusely by primary cutaneous adnexal
neoplasms (28). On the contrary, only a small percentage of
cutaneous metastases express CK 5/6 and they usually do it
in a weak way (28). Even so, these findings are not specific,
and by no means CK 5/6 can be the only marker in which a
diagnosis should be supported.
Mammaglobin is a 93 aminoacids protein which originally
was identified in breast carcinoma cell lines (12).
Mammaglobin is secreted as a glycosylated peptide (10). The
expression of mammaglobin has been described in other
Table 1: Details about the cases investigated for expression of mammaglobin
CAC: cutaneous apocrine carcinoma; ICB: infiltrating carcinoma of breast
CaseGenderAge (years) Type of tumor VariantLocation
1 Female42 CACTubularAxilla
2 Female62 CACCribriform Fossa poplitea
3Female 63 ICBDuctal Skin of breast
4 Female 81ICB DuctalSkin of breast
5Female 70ICBDuctalPre-sternal area
6Female 96ICB DuctalLeft axilla
7 Female 57ICBDuctalSkin of breast
8Female 75 ICBDuctal Skin of breast
9 Female75 ICBDuctalSkin of breast
10Female 56 ICBDuctal Skin of breast
11Female 59ICBDuctal Axilla
12Female74ICBDuctal Left axilla
tissues apart from breast, like lung tumors, tumors from the
female genital tract (16, 29, 33), salivary gland tumors (29),
and malignant mesothelioma (8). Mammaglobin is also
expressed by eccrine and apocrine sweat glands (12), but the
expression is quite different from the one observed in breast
tissue. While eccrine glands show strong cytoplasmic staining
of the coiled cells, in the immunohistochemical study for
mammaglobin, the apocrine glands showed only staining of
scattered cells (31).
Logically, this pattern might be expected for adnexal tumors
of apocrine origin. For instance, cylindroma has been negative
in most cases in which mammaglobin has been investigated,
and when positive, only a small group of cells expressed the
marker (31). Apocrine hidrocystoma showed a pattern of
staining similar to the normal apocrine gland, i.e. just some
scattered cells were positive (31); and the same pattern was
the one observed in hidradenoma papilliferum (31). This is
quite different from the pattern of staining that is observed in
the adenocarcinomas developing from the breast, in which an
intense and diffuse expression for mammaglobin is quite the
rule (38). CAC, on the contrary, has not been investigated till
now for mammaglobin expression, to the best of our
knowledge, but the differences in expression by the breast
tissue and apocrine tumors make us think that it could be one
of the first reliable markers in the differential diagnosis when
facing a possible CAC.
Our results seem to indicate that some additional help in
the differential diagnosis between these entities could be
obtained from the use of this marker when facing difficult
cases. This opinion is in a way contrary to what has
previously been claimed in literature. Bhargava et al., for
instance, asserted that “mammaglobin does not seem to be
a useful stain to distinguish breast from sweat gland
carcinomas” (6). Nevertheless, they do not specified the type
of sweat gland carcinoma studied in their report. That
information is important, not only because the CAC is the
most difficult to distinguish from a metastasis, but also
because mammaglobin is strongly expressed by the normal
eccrine gland (31).
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Angel Fernandez-Flores, MD, PhD
S. Patología Celular
Avenida Galicia 1
Telephone: (00 34) 987 42 37 32
Fax: (00 34) 987 42 91 02
Bohužel nedokonalé snímky z dob 1. světové války pocházejí
z pardubické válečné nemocnice, která stála na místě dnešní čtvrti
Dukla a přilehlých ulic, včetně jižní části nádraží.
Na prvém snímku je vlastní válečná nemocnice; šlo o obrovské
zařízení pro 10 tisíc raněných a nemocných z celého tehdejšího
Rakouska-Uherska. Zdravotnického personálu a vojáků tam sloužilo
kolem 2800. Vedle desítek nemocničních baráků tu byly další budovy
– operační sály, bakteriologie, patologie, lékárna a dále obrovská prá-
delna (sloužila pak přes 50 let pro pardubickou posádku) atd. Nemoc-
nice měla i svoji železniční vlečku.
Neuvěřitelně masový nápor nemocných a raněných zaskočil všech-
ny tehdy válčící státy především tím, že nastal kritický nedostatek
odborného zdravotnického personálu, především lékařů.
Prof. Jaroslav Hlava (1855, Dolní Královice – 1924, Praha) byl
jedním z odborníků, které tehdy úřady pověřily, aby vytvořili koncep-
ci organizace obrovitého nemocničního areálu. Na druhém snímku je
dvorní rada prof. Hlava, spolu s postaršími pány MUC. Fialou
a MUC. Drábkem. Armáda tehdy zmobilizovala i takové, kteří kdysi
absolvovali alespoň nějaký ten semestr medicíny; tito muži zastáva-
li lékařská místa.
Na závěr připomeňme několik dat za života prof. Hlavy: již během
studia na pražské lékařské fakultě začal pracovat na patologické ana-
tomii u Edwina Klebse. Po promoci stážoval v Německu (u Rudolfa
Virchowa) a ve Francii. Po rozdělení pražské Karlo-Ferdinandovy uni-
verzity na českou a německou v roce 1882 se stal prvním přednostou
českého patologického ústavu. Habilitoval se již v roce 1883 a řádným
profesorem byl jmenován roku 1887, jako 32letý. Od roku 1897 až do
své smrti byl předsedou Spolku českých lékařů. Po vzniku ČSR stál
v čele Státní zdravotní rady. Zasloužil se o výstavbu moderního pra-
coviště patologie (1921) – dnešního Hlavova ústavu.
RNDr. M. Vostatek
PROF. HLAVA V PARDUBICÍCH