Secretory Carcinoma of the Breast
F. A. TAVASSOLI, MD,’ AND H. J. NORRIS, MDt
Nineteen examples of a very rare type of carcinoma of the breast have been studied. The carcinoma is
unusual in that it has exaggerated secretory features previously reported only (with one exception) in
juveniles. But not all the patients in our series were juveniles; they ranged in age from 9 to 69 years
(median age, 25 years). Six were 30 years of age or older. Eighteen patients were female and 1 was a
9-year-old boy. Treatment varied from local excision of the tumor to radical mastectomy. Four of the
11 patients who had axillary node dissection had metastatic deposits showing the same secretory features
as the primary neoplasm. One of these 4 patients, a 25-year-old woman, died within ten months with
disseminated tumor. Because this distinctive pattern of carcinoma is not limited to children and adoles-
cents, we propose that it be called “secretory carcinoma.” Since, of the 19 patients, 4 (21%) had axillary
node metastases and 1 (5%) died with disseminated tumor, an extended simple mastectomy is recom-
mended as the inital treatment for patients more than 20 years of age.
Cancer 45:2404-2413, 1980.
I common variety of mammary carcinoma in children
which they designated “juvenile car~inoma.”~ Two
distinctive features characterize this neoplasm: 1) the
presence of large amounts of intracellular and extra-
cellular secretions; and 2) the granular eosinophilic
cytoplasm of the cells. These neoplasms had a less
aggressive behavior and a better prognosis in the 7
children reported than the usual breast carcinoma;
hence, a conservative surgical approach (local ex-
cision) was advocated as treatment. Since then, two
reports have described metastasis to axillary nodes and
one local re~urrence.~~~
Also, we have observed the
same pattern in adults. Therefore, we recommend that
the descriptive term “secretory carcinoma” replace
the designation of “juvenile carcinoma.” In order to
better define the clinical spectrum and behavior of this
distinct entity, 19 examples of secretory carcinoma
are described below.
N 1966, MCDIVITT
AND STEWART described an un-
Materials and Methods
Nineteen examples of pure secretory carcinoma of
the breast accessioned at the Armed Forces Institute
From the Department of Gynecologic and Breast Pathology,
Armed Forces Institute of Pathology, Washington, D. C.
* Vice Chairman, Department of Gynecologic and Breast
t Chairman, Department of Gynecologic and Breast Pathology.
Address for reprints: F. A. Tavassoli, MD, Armed Forces
Institute of Pathology, Washington. D. C. 20306.
Accepted for publication May 18, 1979.
The opinions or assertions contained herein are the private views
of the authors and arc not to be construed as official or as reflecting
the views of the Department of the Army or the Department of
of Pathology over a 16-year period were reviewec
Six other carcinomas having the same secretor
features were excluded because of the presence o
small areas of typical infiltrating duct carcinoma
Clinical information was abstracted from the patients
charts, and the gross and microscopic features were
analyzed. Microscopic sections of the primary tumor
were examined in each instance. A variety of special
stains including mucicarmine, periodic acid-Schiff
(PAS) with and without diastase, alcian blue with
sialidase digestion, alcian blue-PAS, and toluidine
blue at pH 1.5 were used in 3 selected cases (cases 4,
9, 18) in order to determine the nature of the secretory
material (Table 1). In two of these (Cases 4,9), staining
with oil red-0 for fat was also done. Staining with
mucicarmine and PAS with and without diastase was
done in two additional cases (Cases 5, 10) (Table 1).
In addition to light microscopic examination, one
neoplasm was studied by transmission and scanning
electron microscopy (SEM). For examination by trans-
mission electron microscopy, samples of tissue were
retrieved from formalin, fixed in 5% glutaraldehyde,
post-fixed in 2% buffered osmium tetroxide, and em-
bedded in Epon after dehydration in graded alcohols
and propylene oxide. The sections were than cut on
an LKB ultratome, stained with uranyl acetate lead
citrate and examined in a Zeiss 9s-2 electron micro-
scope. For examination by SEM, tissue was removed
from formalin, fixed in 2% glutaraldehyde, and after
dehydration through graded acetone, critical point-
dried with liquid CO,. A plasma coating of a 60:40
mixture of go1d:palladium was applied, and the speci-
men was examined in an AMR-1000 SEM at 20kV.
0008-543)3/80/0501/2404 $0.70 D American Cancer Society
Tavassoli and Norris
TABLE 1. Treatment and Follow-up Information
metastasis Case Treatment Recurrence
Mod. radical mast.
+ (8/ 14)
1 . 5
Mod. radical mast.
Simple mast. 3150 rad
Mod. radical mast.
Mod. radical mast.
Mod. radical mast.
NE = not examined. Mast. = mastectomy; Mod. = modified
One case in this study has been the subject of a
recent report, but the other 18 have not been reported
The ages of the patients ranged from 9 to 69 years
(median, age, 25 years). The youngest was a 9-year-old
boy. Only one patient was premenarchal. Seventeen
(89%) of the patients were white and 2 (11%) were
black. In 11 cases, the neoplasm was located in the
right breast and in 8 cases, the left breast. The dis-
tribution within the breast was not unusual, but three
were subareolar in location and one was located in
the axillary tail of the breast. Eighteen of the patients
presented with breast masses; 1 had a bloody dis-
charge from the nipple. Five patients were taking oral
contraceptive steroids; none was pregnant or had any
evidence of an endocrine abnormality, and none had
Gross Pathologic Findings
The tumors ranged in size from 1 to 12 cm (median
size, 3 cm). They were all firm discrete lesions, ap-
pearing as irregular densely fibrous masses, often
simulating fibroadenomas. Typically, they were
grayish-white or yellow to tan in color and were well
delineated, except in 4 cases, in which the neoplasms
each had an infiltrating margin as seen on gross ex-
Microscopic Puthologic Findings
Two cell types could be distinguished and were
arbitrarily designated as Types A and B, on the basis
of variations in the cell cytoplasm and distribution of
secretory material. Type A cells were slightly granular
and there was abundant secretory material within in-
dividual tumor cells and in extracellular lumens (Fig. 1).
Type B cells were round to polygonal in shape with
finely granular or vacuolated cytoplasms (Fig. 2). An
admixture of the two kinds of cells was always present;
in 4 cases, the neoplasms were predominantly com-
posed of Type A cells and in 7, of Type B cells. In
the remaining 8 cases, the neoplasms were composed
of equal admixtures of both cell types.
Cellular atypism and mitotic activity were minimal
or absent in both Type A and B tumor cells. Seventeen
tumors each had an admixture of an intraductal com-
ponent and sheets and cords of tumor cells (Fig. 3).
Two other neoplasms had basically a lobular configura-
tion. In these, multiple lobules were distended by
tumor cells with coalescence of lobules in some areas.
Two neoplasms'were multifocal. Although all but four
were grossly circumscribed, microscopically all neo-
plasms had irregular margins and focal areas of in-
filtration with irregular extension of tumor cells into
the stroma. Seven neoplasms each had a prominent
CANCER May I 1980
sclerotic or fibroblastic stroma separating the nests
and cords of tumor cells, and six neoplasms each had
a prominent rnyxoid stroma. Six had central papillary
areas. Two neoplasms each had a prominent lympho-
cytic infiltrate with germinal center formation, while
five had focal or sparse lymphocytic infiltration.
The secretory material was positive when stained
with PAS, but it was not digested by diastase and
FIG. 1. Case 3 (Table 1). Abundant
secretory material in both extracellular and
intracellular locations (Type A cells) (H & E,
therefore was not glycogen. The alcian blue with and
without sialidase showed a blue staining, indicating
the presence of sulfated mucopolysaccharides. The
alcian-blue-PAS showed basically a blue-violet re-
action, the result of the presence of sulfomucins, and
some red-violet staining secondary to the presence of
sialomucins. With the toluidine blue stain at pH 1.5,
some of the secretory material showed metachromasia,
FIG. 2. The predominant cells have clear
or granular cytoplasm (Type B cells). A duct
is entrapped by neoplastic cells (H & E, x 250).
. Tuvassoli arid Norris
FIG. 3. Infiltrating cords of tumor cells
surround intraductal carcinoma(H & E, ~ 6 0 ) .
indicative of sulfomucins. None of the special stains
showed uniform staining of the secretory material.
Therefore, although the majority stained as sulfated
acid mucopolysaccharides, some persistently stained
as a sialomucin. The staining reaction with mucicar-
mine varied from case to case, but usually a few cells
were positive, particularly those of the Type B cell
population. Some of this variation may have been due
to variability in the initial fixative. Two neoplasms
with granular or amphophilic cells having foamy cyto-
plasm were stained for fat but were found to be nega-
tive. One neoplasm had atypical ductal and lobular
hyperplasia in the adjacent breast tissue. The unin-
volved breast tissue did not show a secretory effect
in the ducts and lobules, but the stroma showed prom-
inent periductal and perilobular myxoid changes in
Metastatic lesions in axillary nodes had abundant
FIG. 4. Case 3 (Table 1). Lymph node with
metastatic tumor having the same pattern as
the primary mammary tumor: secretory
material distending the extracellular lumens is
apparent (top) (H & E, x 160).
May 1 1980
FJC. 5. Case 3 (Table 1). In a neoplasm composed mainly of Type A cells with abundant secretory material, extracellular lumens (arrows)
are filled with a densely granular secretory material with an electron-dense central sphere. The intracytoplasmic lumens, in contrast, contain
a less dense secretory material which lacks the electron-dense central spherical bodies (X3100).
secretion and a pattern similar to that of the primary
tumor (Fig. 4). A carcinoma that recurred in an ex-
cision scar was less differentiated in the recurrence,
but it maintained its histologic features and contained
abundant secretory material.
Transmission electron microscopic evaluation of a
neoplasm composed predominantly of Type A cells
(Case 3, Table l), showed cells of varying sizes and
shapes depending on the amount of intracytoplasmic
secretory material. The cells were arranged in well
defined clusters and were attached to each other by
desmosomes and interdigitation of cytoplasmic proc-
esses. Lumens were numerous within the neoplastic
cell clusters (Fig. 5). Intracytoplasmic lumens were
also numerous and were filled with diffusely dispersed
granular material. Numerous microvilli projected into
both the intracellular and extracellular lumens (Fig. 6).
The extracellular lumens were frequently several
times the size of even the largest intracellular lumens.
Microvillous cytoplasmic processes were also present
in numerous areas around the cell membrane and these
interdigitated with similar processes of the adjacent
cell, traversing a distinct intercellular space filled with
secretory material (Fig. 7). The intercellular spaces
communicated with the large extracellular lumens
filled with abundant secretory material. The extra-
cellular lumens contained uniformly dispersed moder-
ately electron-dense granular material in which there
were prominent spherical electron-dense bodies. The
clusters of neoplastic cells were partially surrounded
by a well defined continuous basal lamina (Fig. 8).
Occasionally, a fibroblast separated the basement
membranes of two adjoining cell clusters, but because
of epithelial density in the sample, normal stroma was
not evident, and the epithelial-stromal junction could
not be evaluated. There were no myoepithelial cells.
The neoplastic cells frequently had empty dilated
cisterni; the Golgi apparatus and rough endoplasmic
reticulum were prominent in each of many cells. Both
round and tubular mitochondria were present. Lipid
droplets were present in a few cells (Fig. 9). The
nuclei were mainly oval with an occasional indentation,
and nucleoli were also present.
Scanning electron microscopic examination of Case
Tavassoli and Norris
FIG. 6. Case 3 (Table I). Several intracytoplasmic lumens with numerous microvilli displace the cell nucleus to the periphery. Multiple
desmosomes (arrows) connect the cytoplasmic membranes of adjacent cells ( x 15,000).
3 (Table 1) revealed that the size and shape of the
tumor cells varied greatly. Some cells had microvilli
projecting from the cell surface, while others were
distended by secretory material and had bulging flat
surfaces with fewer microvilli. Occasionally, a cell
appeared collapsed with prominent folding of the mem-
brane (Fig. 10).
Treatment and Follow U p
Treatment and follow-up information for the 19 pa-
tients is presented in Table l . Four of the 12 patients
who underwent axillary node dissection had metastasis
to one or more nodes (Table 2). The 26-year-old pa-
tient in this group (Case 3, Table 2) was initially treated
by means of local excision and eight months later a
recurrence developed. A radical mastectomy was per-
formed at this time, and three of the low axillary nodes
contained metastatic tumor. She was then given a
course of cytotoxic chemotherapy; the type and dosage
of the agent used are not known. There was no further
recurrence in the ten months following her radical
The period of follow up ranged from a half to 12
years (median time, six years). There were 4 patients
with less than five years of follow up, which is too
short a period for evaluation of progression of the
disease. One paticnt was lost to follow up.
The age of the patient may be an important factor
in the progression of the disease, as 4 of the patients
treated by means of local excision were 2 1 years of age
or younger and, although the period of follow up is
short in 3 cases, there has been no recurrence six
months, 21 months, three years, and ten years after
excision. One patient, a 10-year-old girl with a 1-cm
tumor, is well without evidence of recurrence eight
years after undergoing a simple mastectomy. Another
CANCER May 1 1980
Flci. 7. Case 3 (Table 1). An intercellular space filled with secretory material separates adjacent tumor cells and is traversed by numerous
microvilli (x 19,500).
patient, a 16-year-old girl with a 3.5-cm tumor, under-
went a modified radical mastectomy and had no posi-
tive axillary nodes. She is alive six years postopera-
tively but nothing more is known of her status. In
contrast, the patients with positive axillary nodes were
24, 25, 26, and 45 years of age (Table 2).
Tumor size was related to the likelihood of nodal
metastasis. None of the five neoplasms less than 2 cm
in diameter metastasized. The smallest tumor that
metastasized to axillary nodes was 2 cm in diameter,
and the largest to do so, was 6 cm. The largest tumor
(12-cm) in the series did not show evidence of axillary
node metastasis, however. The patient was 69-years
old and was treated by means of a modified radical
mastectomy. The gross margin of the tumor was of
prognostic significance since only one of the four neo-
plasms with nodal metastasis appeared grossly cir-
Whether the neoplasm was composed predominantly
of Type A or B cells was of no prognostic significance,
as, of the tumors that metastasized to axillary nodes,
two were mainly composed of Type A and two of Type
B cells. The two cell types are emphasized because
they are distinctive and pathologists should be aware
A lymphocytic infiltrate with prominent germinal
center formation was found around the tumor in 2 pa-
tients. One, a 10-year-old girl, is well eight years
after undergoing a simple mastectomy for a tumor 1 cm
in diameter. The other, a 28-year-old woman treated
by means of radical mastectomy, did not have axillary
metastasis and is alive eight years postoperatively.
The patient with the longest survival time (12 years),
however, had no lymphocytic infiltrate within or around
her tumor. She was 30 years of age, was treated by
means of radical mastectomy for a 1 cm tumor, and
had no axillary node metastasis.
Family histories were available for 3 patients. The
only patient with a positive family history is also the
only one who died with disseminated tumor. She had
CARCINOMA Tavassoli and Norris
FIG. 8. Case 3 (Table 1). Basement membrane partially surrounds nests of neoplastic cells ( ~ 6 , 5 0 0 ) .
a neoplasm 6 cm in diameter, and 8 of 14 axillary nodes
in her radical mastectomy specimen contained meta-
static tumor (Case 2, Table 2).
Secretory carcinoma, by ultrastructural analysis, is
unique in the prominence of its intracytoplasmic
lumens and the abundance of the extracellular lumens
containing secretory material. Epithelial cells in benign
lesions such as duct papilloma and many varieties of
breast cancers have intracytoplasmic lumens but not to
the degree found in secretory carcinoma.’.”’ The
minimal or absent secretion in the cells arranged
around the extracellular lumens suggests that these
cells have emptied their secretions into the extra-
The degree of organization in secretory carcinoma
is less than that seen in lactating lobules. Lactating
lobules are composed of numerous distinct acini
(ductules), each having a myoepithelial layer and sur-
rounded completely by a distinct basement mem-
brane.5 Although tumor cells in secretory carcinoma
are arranged around the extracellular secretory ma-
terial in an acinus-like configuration, a myoepithelial
cell layer and basement membrane are absent. The
tumor cells do not form any true acini. Carcinomas
in pregnant women do not show the extensive intra-
cellular and intraluminal secretory material present in
secretory carcinomas; the hormonal effect is mani-
fested mainly in the stroma by the presence of a prom-
inent periductal and perilobular myxoid change.R
Among the neoplasms in this study, six had significant
myxoid changes in the tumor stroma. Of these six,
one also had periductal and perilobular stromal myxoid
changes in the adjacent breast tissue as well; the
patient was using oral contraceptive steroids. Another
4 patients each had a myxoid change in the stroma
of the normal breast tissue only, apart from the tumor,
in mainly a periductal and perilobular distribution.
Three of these 4 patients were taking oral contraceptive
steroids. The youngest patient with a myxoid change
in the stroma of the neoplasm or the adjacent breast
tissue was 17 years of age, and the oldest was 42 years.
Although the special stains indicate that the secre-
CANCER May 1 1980
FIG. 9. Case 3 (Table I). A cell with a lipid droplet ( x 18,500).
tory material is an acid mucopolysaccharide and mainly
in sulfated groups, not all of the secretions stained
uniformly with the various stains. The major part of
the secretion in the extracellular spaces had a different
electron density as compared to that of the intracellular
secretions. Electron-dense spherical bodies were
prominent in the extracellular lumens, but only rarely
did the intracellular secretions contain a dense spherical
central component. This could be a result of a difference
in the ratio of the protein and carbohydrate concentra-
FIG. 10. Case 3 (Table 1). The cell surface
patterns reflect the variation in the intra-
cytoplasmic accumulation of secretory
material; the cell membranes flatten with
increase in the intracytoplasrnic secretory
SECRETORY CARCINOMA . Tavassoli and Norris
TABLE 2. Patients with Axillary Node Metastasis
Size of tumor
(cm) Case Race Follow-up, timc after diagnosis
3 of 11
8 of 14
1 of 20
Well, 6 years
Died with metastatic tumor, 10 months
Local recurrence, 8 months; NED, 18 months
Well, 5 years
NED = no evidence of disease; B = black; W = white. Cell types described in Materials and Methods.
tions in the intracellular and extracellular secretory
material. The possible presence of casein in these
tumors should also be investigated in the future.
Secretory carcinoma is a separate entity from the
lipid-rich (lipid-secreting) carcinoma because two neo-
plasms stained with oil red-0 did not contain stainable
fat and ultrastructural examination showed only an
occasional lipid droplet in the tumor cells.9 Further-
more, the neoplastic cells contained PAS, alcian blue,
or mucicarmine-positive material, features contrary to
Secretory carcinomas are distinct from mucin-pro-
ducing carcinomas (mucoid carcinoma, signet ring cell
carcinoma, and mucin-producing papillary carcinoma)
by the absence of membrane-bound mucin droplets.
In lobular carcinomas, the mucin is confined mainly
to intracytoplasmic lumens,3 but they are not as abun-
dant as in secretory carcinomas. Furthermore, secretory
carcinomas also have an abundance of secretory ma-
terial in the extracellular lumens. Harris c ~ t ~
proposed a possible derivation of the intracytoplasmic
lumens from the Golgi apparatus. They demonstrated
varying degrees of dilatation of the Golgi cisternae
associated with concentric fibrils in the adjacent cyto-
plasm and suggested that, as the Golgi becomes pro-
gressively dilated, the cytoplasmic strands separating
the cisternae become attenuated and transformed into
microvilli. Our findings also support such B derivation.
By means of SEM, the cellular pleomorphism may
distinguish this lesion from some noncancerous lesions
of the breast,h the cell surface pattern, however, cannot
be reliably distinguished from that atypical of apocrine
hyperplasias or various papillary carcinomas.x The
presence of some large cells bulging with secretory
material and about to rupture suggests cell disruption
as a possible mechanism for at least partial discharge
of the secretory material into the extracellular spaces.
Undoubtedly other mechanisms are also involved.
Steroid receptor studies of these tumors would be
of interest for determining whether there is any dif-
ferences between the tumors occurring in the pre-
pubertal patients and those occurring in adult patients
and for determining whether the receptor concentration
is related to prognosis.
Since this neoplasm is capable of axillary node and
distant metastasis. in adult patients, a conservative
surgical approach such as local excision is insufficient
for controlling the progression of the disease. A simple
mastectomy with axillary node dissection will probably
be adequate as the initial treatment for patients more
than 20 years of age, with the necessity for further
treatment dependent on the results of this initial pro-
cedure. Since metastases are so rare in children,
wide excision probably is adequate. As our knowledge
in the field of cancer therapy increases, other means of
controlling the progression of this neoplasm will be-
1. Battifora, H.: lntracytoplasmic lumina in breast carcinoma. A
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2. Byrne, M. P., Fabey, M. M., and Gooselaw, J. G.: Breast
cancer with axillary metastasis in an 8-112 year old girl. Canrer
3 1:726-728, 1972.
3. Harris, M., Vasudev, K. S., Anfield, C.. and Wells, S.:
Mucin-producing carcinomas of the breast: Ultrastructural observa-
tions. Histopathology 2: 177- 188, 1978.
4. McDivitt, R. W., and Stewart, F. W.: Breast carcinoma in
children. JAMA 195:388-390, 1966.
5. Salazar, H., Tobon, H. H.. and Josimovich, J. B.: Develop-
mental gestational and postgestational modifications of the human
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(Juvenile) carcinoma of the breast. Puthology 9:341-346, 1977.
8. Tavassoli, F. T., and Norris, H. J.: Unpublished data.
9. Van Bogaert, L. H., and Maldague, P.: Histologic variants
of lipid-secreting carcinoma of the breast. Virch. Arch. Parhol.
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