Mammary cysts: Pathophysiology and biochemistry

Nucl. Med. Biol. Vo1.14, No.4, pp.397-406,

1987

0883-2897/87

53.0040.00

Pergamon Journals Ltd

Int. J. Radiat. Appl. Instrum. Part B Printed in Great Britain

MAMMARY CYSTS: PATHOPHYSIOLOGYAND BIOCHEMISTRY

Albert0 ANGELI,

Luigi DOGLIOTTI,

Dipartimento

di Biomedicina,

(*) Servizio

di Anatomia

Ravenna,

Fabio ORLANDI and Donatella

Universita

Patologica,

BECCATI*

degli Studi, Torino,

Ospedale

and

S. Maria delle Croci,

Italy.

INTRODUCTION The widely used term ray of clinical

Fibrocystic

and morphological

entities.

fusion since it is applied to pathological

Breast Disease

(FCD) encompasses

a heterogeneous

ar-

It is agreed that in itself the term can lead to conpictures that are both multiform

and subject to change

in the course of time. The lack of agreement

in defining

(1982) has cast doubt on the very existence ticles have suggested

to abandon

FCD is such that a provocative of FCD as an independent

"tout court" the term. In 805,

componefits has been the focus of considerable some components with breast carcinoma. with FCD have a significantly

attention

Epidemiologic

article by Love et al.

entity. Afterwards,

dissecting

in view of the possible

studies,

higher risk of later developing

other ar-

FCD into homogeneous relationship

in fact, have revealed

of

that women

breast cancer than control populat-

1983; Mac Mahon -. et al 3 1973; Page -. et al 3 1978). 1980; Lubin -(Y et al however, have led to the opposite conclusion (Devitt, 1972; Winder et., 1978).

ion (Hutchinson et., Other studies, Pertinently, clinical

it was suggested

and prognostic

sen et al., 1~81) withstanding

that any classification

aspects,

these uncertainties,

College of Georgia,

New York (Haagen-

disorder of the hormonal

Atlanta

information

to breast cells in women of

age.

Gross Cystic Disease 1986).

of FCD should take account of pathological, at the Columbia University,

1984). Not(Greenblatt -., et al it is agreed that from a pathophysiological viewpoint, FCD is

and at the Medical

the result of a multifactorial childbearing

as it was attempted

It is a common condition:

(GCD) is thought to represent an advanced form of FCD (Vorherr, some 7 per cent of women

in the western world develop a palpable

breast cyst (Haagensen -.1 et al 1981). Clinically evident macrocysts (>l cm diameter) develop main ly in the premenopausal decade; their appearance and local pain depend on the degree of fluid filling

and pericystic

stromal fibrosis.

Two fundamental

subserved

isolated

lesion; in this case, it is viewed as the consequence

which

by different mechanisms

clinical pictures

possibly

in turn leads to retention of secretory material

"Obstructive" multiple, micro-

complemented

and macrocysts

quently

in this case, they conceivably

by hyperplasia

and papillarity

can be distinguished,

A cyst may present as a clearly of duct obstruction

by fibrosis,

and dilation of terminal ducts and alveoli.

cysts usually do not recur after aspiration.

often bilateral;

secretion,

Alternatively,

cysts may present as

depend on continuous

of the epithelium,

due to impaired drainage of the supervening

ductular-alveolar

which

in turn lead to

fluid. 'Secretory"

cysts fre-

recur after aspiration. Cysts are not considered

patients

are at two-four

This assumption presence exclude,

has recently been questioned

lesions. However, several reports 1979; Haagensen

et -.

indicate that al

)

1981a).

by DuPont and Page (1985), who reported that the

that the major determinants

of the risk were hyperplastic

however, that these lesions were specifically

cysts, not separately

designated

Since the majority aspiration, are

premalignant

fold higher risk of cancer (Azzopardi,

of cysts doubled the risk only in women with a family history of breast cancer. They

demonstrated

women

of cyst formation.

pathological at

greater

risk.

lesions; they could not

associated with particular

subsets of

in the study.

or women with breast cysts are not biopsied but treated by simple

diagnosis

is

rarely

available

In the most recent years,

fered by studies on the composition

of the aspirated

397

and novel

fluid.

it

remains

approaches

uncertain

which

of

these

to the issue are being of-

A. Angeli et al.

398

HORMONAL COMPOSITION Detailed analyses piration,

have documented

of breast cyst fluid

that this "biochemical

(Bradlow et,

1985). Chemical

trace elements,

proteins,

components

tumor associated

The first observation

(BCF), which

is easily obtainable

space" is indeed a storehouse

concerning

of BCF that have been studied antigens,

investigated

the impressive accumulation

the hormonal

present

include electrolytes

and

content of BCF dates back to 1973, when Later, the androgen composition

by Bradlow et al. (1976, 1979, 1981), who called attention

in this medium of sulfate conjugates

sulfate, DHA-S). On these grounds, and estrone conjugates

unusual

enzymes and hormones.

(1973) reported high levels of 17-ketosteroids.

of BCF was extensively

by needle as-

containing

a number of them not found in the blood of healthy women

levels of a wide variety of substances,

Fleischer et

OF BREAST CYST FLUID

it was suggested

that the exceedingly

in BCF are the result of aromatization

of these androgen precursors the classical estrogens

(Hawkins -.* et al 1985; Raju -. et al or their sulfates exhibited significant

after their intravenous

infusion

in radioactive

on

(first of dehydroepiandrosterone high amounts of estriol

and hydroxilation

in loco

1977, 1985). In fact, none of

I

accumulation

form, although the majority

in the cyst fluid of these steroids

1981). Besides several unusual steroids and condisplay a high BCF to blood ratio (Raju -., et al relevant to androgen and estrogen action, BCF contains also progesterone, 17-hydroxypro-

jugates

gesterone

and all major corticosteroids.

The concentrations

of these hormones have been found

1983; Bradlow -. et al (Melis -.) et al in BCF are summarized in Table I.

higher, similar to or lower than in blood plasma sonal data on steroid hormones

Table

I. Steroid Hormones No.

Median

pmol/l

54

95.7

Androstenedione

nmol/l

69

6.49

Cortisol

nmol/l

285

99.32

Range 34.7

- 208.1

0.69 -

23.92

11.03 - 336.58

DHA

nmol/l

75

26.69

1.21 - 102.28

DHA-S

kmol/l

409

97.27

1.29 - 115.43

Estradiol

pmol/l

182

403.8

36.7 - 1652.1

Estrone

pmol/l

76

314.3

36.9 - 2441.18

Progesterone

nmol/l

266

40.70

Testosterone

nmol/l

124

4.16

1.04 -

13.17

17-OH-Progest.

nmol/l

133

14.82

1.51 -

24.81

as to the applicability

2.54 - 103.67

to the cyst fluid or procedures

sed for blood plasma do not seem to hold; in our lab, validation thought to be satisfactory

on the basis of serial dilution

ing is the fact that most of the steroid molecules

in BCF are in their free, non protein-

specific

in BCF did indeed yield values not exceeding

counterpart

(Bradlow et.,

trations,

devi-

and recovery studies. Worth interest-

present

available

eluded, therefore,

originally

of the chosen procedures was

bound form, and hence immediately steroid binding proteins

1983). Per-

in BCF

Aldosterone

Uncertainties

3

for cellular penetration

and action. Quantitation

of

l/10 of the plasma

1981; Frairia -.3 et al 1983; Rosner -. et al 3 1985). It could be conactive steroids are present in BCF in unusually high concen-

that biologically

complemented

by an intriguing pattern of conjugates

and metabolites,

the significance

of which awaits investigation. As far as pituitary gonadotropins,

prolactin

1984a,; Bradlow et,

hormones are concerned,

and thyrotropin

appreciable

1983). Personal data on pituitary Table

amounts of growth hormone

(TSH) have been repeatedly

II. Pituitary No.

hormones

Hormones

reported

in BCF are summarizedinTable

which

Range 4.2

0

GH

w/ml

40

TSH

pIU/ml

45

2.3

0.5 -

FSH

mIU/ml

40

2.1

0

-

6.6

LH

mIU/ml

40

3.3

0

-

8.4

PRL

w/ml

412

5.6

1.0 -

41.6

in our series displayed

in 8CF deserves

special

(T4), total and free tri-iodothyronine

(TBG), TSH and prolactin

in 8CF and coincidental

(Angeli -. et al 1 1984b). Mean or median

6.8

yet being at variance

for

a median value lower and not higher than in plasma.

The profile of thyroid hormones tal and free thyroxine

II.

in BCF

Median 1.1

They are in rough accord with those of other investigators, prolactin,

(GH),

(Angeli et al.,

interest. We measured

(T3), thyroxine-binding

both to-

globulin

blood samples coming from 73 premenopausal

levels are presented

in Table

III.

women

VIIth International Symposium on Radioimnunology

Table

Thyroid Hormones

III.

in BCF

No.

Median

nmol/l

225

7.37

0.61 -

41.16

T4

nmol/l

98

20.56

2.57 -

59.12

FT3

pmol/l

164

111.21

FT4

pmol/l

162

123.39

rT3

nmol/l

50

4.91

in most cases (P
T3

ly correlated

with log-prolactin.

vious experimental thyroid hormones

Range

T3

In BCF, both free T4 and free T3 were consistently

was also total

Interestingly

abnormally

1979; Mittra et,.,

7.98 - 296.46 1.06 - 524.42 2.15 -

higher than in plasma

enough,

intracystic

sensitize mammary epithelial

to dysplastic/neoplastic

in the light of pre-

cells to prolactin

transformation

pathological

in concert; our data, furthermore,

provide support to historical

activity,

stimulation,

(Bhattacharya

1974). Our data do not contrast the possibility

to do with proliferative

(P
free T3 was inverse-

that through changes in prolactin-binding

breast, at least in the particular tion has something

11.98

This latter finding has to be considered

studies, which suggested

ting the susceptibility

Vorherr,

399

augmen-

and Vonderhaar,

that also in the human

model of GCD, thyroid hormones observations

and prolactin

act

that thyroid func-

breast lesions and cancer risk (Hedley -. et al

9

1981;

1978). CATIONS, DHA-S AND CATEGORIZATION A cationic

reported

composition

of BCF resembling

OF CYSTS

that of the "intracellular"

by Fleisher et al. (1973) a number of papers have then appeared

pect. Generally

speaking,

as-

of cations higher than in plas

of Cl- and HC03- lower than in plasma, so that the routinely performed

ma and concentrations culation

it is agreed that BCF has concentrations

milieu was first

on this particular

of anion gap often results in surprisingly

high values.

In

addition,

cal-

a growing body of

knowledge

indicated that BCFs are quite different with regard to their cationic pattern and that

measuring

ions in BCF is of value to identify subgroups We measured

the intracystic

concentrations

with those of DHA-S (radioimmunoassay) well documented and repeated

GCD.

In all patients

clinical examination.

the menstrual

patients.

Scatterplots intermediate

cancer was excluded

quadrants

sonography, mammography

in the follicular

from women in documented

of the same or controlateral

of K+ fi Na+ demonstrated

the existence

subdivision

was statistically

in these 3 categories IV. Differences

validated

type

III

cysts

by the Bartlett's

is shown in Table

cysts aspirated

of two major subsets and a third

have intermediate

from patients

Luteal Phase

Menopause

73 cases

53 cases

55.9 %

57.5 46

35.8 %

33.8 %

36.9 %

56.6 %

III. Kt/Nat 0.66 + 1.5

10.2 %

5.4 %

7.5 %

(chi-squared

follicular

B

luteal: n.s.

follicular

E

menopause:

luteal vs menopause: In comparable classification

cysts of

in the

test)

p < 0.001

p < 0.001

studies by Bradlow et.

(1983) and by Miller et al. (1983) a similar

was found, even though the boundary values chosen were somewhat different Table V. Cations No. of samples

GROUP (from Bradlow -.) et al I. K+>lOO; Nat>50

(mEq/l)

II. Kt<50; Nat>100

(mEq/l)

assayed

1983)

III. Kt and Nat<100 and X0

II

This

patients.

Kt/Nat < 0.66

% distribution

type

levels.

test (p
cycle and from menopausal

420 Cases I. Kf/Nat > 1.5

on

IV.

Follicular Phase

II.

phase of

luteal phase; 53 came

breast.

in cation patterns of BCF samples aspirated

and luteal phase of the menstrual

together

from 474 patients with

set. Type I cysts have high K+ low Na +, high DHA-S (K+/Na+>l.5);

our samples

follicular

by thermography,

Our samples were collected mostly

have high NA+, low K+, low DHA-S (K+/Na+<0.66);

Table

of BCF aspirated

120 samples came from 53 patients bearing multiple

the same day in different minor

in 546 specimens

cycle (no. 420); 73 were aspirated

from menopausal

of patients with GCD.

of K+ and Na+ (flame photometry)

(mEq/l) Total

(X)

327

(58%)

121

(21%)

118 (21%) 566 (100%)

(Table@

in BCF GROUP

No. of samples

(from Miller -.) et al I. K+/Na+ > 1

1983)

47

II. K+/Na+ < 0.25

III.

assayed 43

K+/Na+ > 0.25 < 1

10 Total

100

(%)

A.

400

Angel I

et

~1,

Our studies on 8CF cations and DHA-S are reported 1986a; Orlandi et.,

large series the wide biochemical type distribution

heterogeneity

was apparent when considering

phase of the menstrual

bearing multiple

aspirated

supports

involving the dysplastic

events. No apparent correlation

were evaluated

vs luteal

was found bet-

different

cysts aspira-

is the consequence

as inferred by the Quetelet's

parenchimal

patterns

at blind by a well trained radiologist

as dysplasia

PI and P2 codes was substantially

in the major

tissue in a general way and does not reflect simply local

Wolfe's

Only 4 cases were classified

difference

characterized

was found between body adiposity.

DHA-S or Kt/Nat ratio. Mammographic

classification

difference

in the follicular

the view that BCF composition

index, and intracystic

although

(Dogliotti et al.

(Table IV). While in the former population type I cysts in the latter they were the minority. In about 70% of

cysts, the same cationic pattern

ted on the same day. This homogeneity of mechanisms

of BCF. No significant patients

cycle; on the other hand, a highly significant

ween menstruating vs menopausal patients (high Kt; high DHA-S) were the majority, patients

in detail elsewhere

1987). Here, we summarize the findings as follows. We could confirm on a

(DY); they all beared type

comparable

I

according

to

in 319 patients.

cysts. The distribution

in breast tissues homing cysts of different

of

types,

a trend was apparent towards a higher number of P2 codes in breast with type I cysts

(Figure 1). Taken together,

our data do not confirm the apparent

association

between mammographic

risk and type I cysts as reported by Pye et al. (1984). The most important finding.

however, was the demonstration

sitive correlation

between

intracystic

ther investigation

on the relationships

between DHA-S, cations and the so-called

sia of cells which line the cysts: data have been published, centrations Miller -. et al

of DHA-S are specifically

)

of a highly significant

DHA-S and the K+/Na+ ratio (p
apocrine metapla

in fact, which suggest that high con

associated with apocrine

secretion

(Labows -. et al

)

1979;

1986).

l4OLFE CODES AND CYST TYPE NW 90-

80786050483aa ifin

Figure 1. Percent distribution patients with different

of mammographic

cyst types.

patterns

po-

fur-

according to Wolfe's

codes in 319

Vllth International Symposium on Radloimnunology

APOCRINE In a recent publication epithelium:

CELLS IN BCF

the cyst type was correlated with the morphology

high K+ cysts (type I) were found to be specifically

thelium: whereas

1983). This dichotomy,

however,

of the lining

associated with the apocrine ep1

low K+ cysts (type II) were lined by flattened

ges (Dixon a.,

401

cells with minimal

has already been questioned

apocrine chan-

(Page and DuPont,

1986). We examined from 39 premenopausal submitted).

the morphology

5,820 apocrine

quantitative

of the apocrine cells present

patients with a history of two simultaneous cells belonging

computer-aided

Leitz-Texture

to well defined Analysis

in 78 BCF specimens obtained

aspirated

System

(TAS) (Nawrath and Serra, 1979). They

came from 57 cysts. The contour of each cell was traced on the TAS monitor surface areas of cytoplasm,

nucleus and nucleolus

lated the nuclear/cytoplasmic factor

have been measured

(N/C), the nuclear/nucleolar

(RF). This last parameter,

the degree to which the nucleus

calculated

cysts (Beccati et.,

cellular clusters were studied by a by a light pen; the

and then the computer

by the formula perimeterz/area

in cross section approximates

x 4 TT was defined as

a perfect cyrcle

1982). 47 samples of type I and 10 samples of type II being submitted was apparent

to the morphometric

between the apocrine

criteria for

no appreciable

this percentage

the 8CF samples coming from type III

for this particular

with a higher frequency of esfoliated Dixon et.

9

difference

cells coming from type I fi type II cysts. However, whereas 84%

cysts. None of

tern) had cell clusters suitable

(Diamond -. et al

cysts met the cytologic

analysis. At the light microscope,

of 8CF coming from type I cysts were "apocrine cell-rich", coming from type II

calcu-

(N/n) ratios and the nuclear roundness

apocrine

computation.

was only 56% of BCF

cysts (intermediate

Our findings

cells in type I cysts, as it was suggested

(1983), yet they do not allow the inference of apocrine changes

pat-

are compatible by

in the epithelium

lining the cysts simply from the cationic pattern of BCF. We believe that the term "apocrine cysts" should be used only after morphologic Cytometric from type type II

measurements

cysts have significantly

I

evaluation.

provided the demonstration wider cytoplasma

(Table VI).

Table VI.

Morphometric

results

in Type I cysts (47 samples) Type I (Mean + SD)

Cytoplasmic Nuclear

area (p2)

area

Nucleolar

(12) (j.i2f

area

Type II

Searching

42.65 + 10.41

41.88 + 10.53

4.35 + .99

2.75 + .71

for correlations

correlated

with the cationic

the differences

different hormonal

functional effects,

Prominent Functional

in turn depending

parameters

levels. The question

in type I g

type II

could be raised

correlation

cysts, possibly

found in secretory epithelial

is actually or potentially

or late steps of the cellular

words,

the cationic accordingly,

quent albeit functionally

different

the issue and to corroborate

reflect

related to cells when

active (Alberts -. et al

life are conceivably

characterized

lesions and increased

type of cysts could be viewed as reflectin the so-called

apocrine or flattened

)

1983).

by the

and/or turnover

risk of later developing

of apocrine

signs of preneoplastic

cancer could be associated with the secretory ac-

significance

this regard, calculation

line are usually devoid of malignant

a fluid with high K+ and

cells in their wall. Hyperplastic

tivity of these cells which per se cannot be viewed as prone to malignant

In

of RF deserved

significance:

proliferation.

was found in our population

In fact,

of about 6,000

value. Round nuclei with regular out-

the circular shape of apocrine cell nuclei

1982) is to be viewed as complementing (RF values near to 1) (Diamond -.* et al examination.

atypia at the light microscope

the activity

cysts could be subse-

stages of a single type. Further work is needed to clarify

the emerging view that the cysts containing

high DHA-S have a higher frequency

cells.

and the K+/Na+ ratio

for the N/C ratio which was inversely

and the above mentioned

are generally

of the lining epithelium;

apocrine

N.S.

of these organelles.

In other

no morphologic

N.S. < 0.05

on the intensity of androgen exposure and/or metabolization.

protein synthesis

exhaustion

volume reduction

parameters

stages of the epithelium

nucleoli and wide cytoplasm

post-trascriptional

r-values

ratio and the androgen-sulfate

in TAS-computed

P < 0.05

.9920 + .0422

between the morphometric

significant

cysts (10 samples)

(Mean + SD)

59.66 + 14.90

.9704 + .0437

and log-DHA-S yielded statistically

and Type II

91.13 + 24.28

RF

whether

that the apocrine cells obtainable

and nucleoli than those aspirated from

the absence of

A. Angeliet al.

4D2

TUMOR ASSOCIATED ANTIGENS

(TUMOR MARKERS)

IN BCF

A number of substances may be found in BCF in different amounts according to the cyst type. Interest in searching for levels of tumor markers has been logically raised by the reported higher risk of breast cancer in patients with GCD. The term of tumor markers conventionally

refers to substances which are released in

the biological media in relation to a given neoplastic process. These substances may be oncofetal or tissue-associated

antigens, hormones or enzymes; they may be specific (strong association with

a particular type of cancer) or non-specific

(relationship with different tumors).

Among oncofetal markers, the carcinoembryonic

antigen (CEA) is not a homogeneous pro-

tein but rather a family of isoantigens expressed by glicoproteins The most characterized glycocalyx

CEA has about 200,000 dalton

molecular

of different molecular weight.

weight; it is secreted onto the

surface of the cells that line the intestinal tract. The presence of CEA-like material

in BCF was first reported by Fleisher et.

(1974); recently, Olivati et.

(1986) have measu-

red the antigen in a series of about 100 BCF samples; levels ranged from 0.6 to 60 ng/ml, whereas in blood samples concomitantly

drawn the mean value was 2.1 + 0.3 SE ng/ml. No correlation was

found between the levels measured in Type II

in the two media. High CEA levels are reportedly more frequent

cysts (Bradlow -. et al ) 1985, Olivati et., 1986). Alpha-fetoprotein (AFP) is a 70,000 dalton molecular weight protein with alpha-elec-

trophoretic mobility.

Elevations in its plasma concentrations

have been found first in patients

with hepatoma and then in patients with a variety of malignant was found to be present

and non-malignant

in consistent amounts in a certain number of type

conditions. AFP

I cysts

(Bradlow et,

1985). The beta-subunit of HCG is normally secreted by the trophoblastic placenta;

it is thought that the presence of detectable

pregnant woman is indicative of underlying tumor. Greenblatt sence of biologically

active beta-HCG at levels > 5 mIU/ml

ples aspirated from 31 patients.

epithelium of the

levels of beta-HCG in blood/of a nonand Mahesh

(1986) reported the pre-

in more than half of the 64 BCF sam-

It was suggested that the high concentrations

could express the production of glycoprotein

of this antigen

hormones in situ by cellular components of the cysts.

We have recently measured the intracystic levels of CA-125. This antigen is associated with a high molecular weight glycoprotein velopment;

expressed

in coelomic epithelium during embryonic ae-

levels of CA-125 are admittedly elevated in blood of patients with epithelial ovarian 1983) and more rarely with other tumors, including, breast carcinoma

cancer (Bast et.,

(Bast

1984). In our series of patients with GCD, the levels of the anti1983, Sarmini -.* et al gen in serum were always in the normal range (mean value: 13.6 + 1.4 SE, range 5-28 IU/ml),

et.,

whereas the levels in about 70% of BCF were exceedingly higher (mean value: 179.0 + 15.9 SE, range 5->>500 IU/ml) (Figure 2). Interestingly enough, the intracystic concentrations

of CA-125 were inversely corre-

lated with the K+/Na' ratio (p
,

ten-fold higher than in plasma (Dogliotti aal.,

in type II

1986b). This pat-

which appears to be in rough parallelism with that of CEA, is in accord with the view that

breast epithelium

has the potentiality

of producing a variety of glycoproteins

other tissues, and raises interest on the significance of these substances tion and proliferation

originally found in

for cell differentia-

.

We think worth mentioning also the occurrence

in BCF of some unusual proteins of poten-

tial value as tumor markers. Haagensen -., et al (1979) analysed in detail the protein content of BCF and identified the new major proteins, which were termed gross cystic disease fluid proteins (GCDFP). Among them, the GCDFP-15 tion in that it demonstrated Matoujian,

(15,000 dalton molecular weight) has received particular atten-

to be specifically

1983). High concentrations

immunohistochemical

associated with apocrine secretion

(Haagensen and

of this antigen were found in axillary and perineal sweat;

staining was strongly positive in breast carcinomas with apocrine aspects,

while it was negative in normal mammary tissue (Mazoujian -. et al ) 1983). The levels of GCDFP-15 in BCF may be as 100,000 times higher than in plasma; moreover, immunoreactivity for this protein was found in a consistent percentage of breast cancer cells and in serum of more than 40% of breast cancer patients prior to chemotherapy

(Mazoujian et.,

intriguing protein in ECF and more generally

in breast fluids (levels in nipple aspirates seem to

1983). The biological

role of this

be similar to those in BCF) is still unknown. CONCLUSION AND PERSPECTIVES Breast macrocysts thogenetic mechanisms. active substances,

are well recognizable entities which possibly depend on different pa-

The fluid filling the cysts (BCF) contains unusual amounts of biologically

including hormones and metabolites.

The measurement

of BCF cations

(K+; Na+)

allows categorization of cysts into two major subsets (type I; type II); these subsets display a different degree and/or turnover of apocrine cells in the lining epithelium.

VIItn International Symposium of Radioimnunology

Figure 2. CA-125 concentration

u*nl 500 1

in 134 specimens

of human breast cyst fluid. 30 U/ml represents the upper limit of normal values

403

in blood

C‘T-12

plasma.

: : I 20(3

Neither

cysts nor apocrine changes have the significance

the term premalignant

means a condition whose natural history

In this regard, our cytometric

of premalignant

as a matter of fact, in the attention was called on the

116 cases of coexisting

apocrine epithelium

being unable to trace the origin of the carcinoma from apocrine epithelium

may occur anywhere

with GCD the greater multiple

risk of later developing

cysts provides valuable

ciated proliferative Turning features

as carcinoma developing

in the breast. Preliminary

cancer is indeed of those who have had single or

information

on a whole-organ

investigation

of the terminal duct-lobular

isting cysts. There is at present reported

conclude, therefore,

promoting

that

status towards asso-

lesions.

to perspectives,

is urgently needed to assess the histological

units (TDLU) in relation to the different subsets of coex-

insufficient

evidence that epithelial

atypia is more closely associated with high K+, apocrine recently

years or even decades after

data indicate that among patients

type I cysts (Dixon et al., 1985a); one could provisionally

categorizing

and carcinoma,

in a single instance.

evidence suggests that cysts and/or apocrine changes may be a marker

of risk within the mammary glands generally, their recognition

if

(1981) on apocrine secretion,

(1932), who described

On the other hand, available

lesions,

involves the evolution to cancer.

data did confirm current knowledge;

leading article of Haagensen et., study of Dawson

:

cell-rich,

type

hyperplasia

I

with marked

cysts as it has been

(Dixon et al., 198513). It is agreed that the normal apocrine glandular

of the body is under the influence of androgens; cretion and BCF are reportedly

similar

interestingly

tissue

enough, axillary sweat gland se-

in their androgen-sulfate

content

(Labows et al., 1979;

Wales and Ebling, 1971). On these bases, work in the next future should be directed to better define the secretory activity possibilities

of apocrine

of processing

cells in response to hormones steroid precursors

(androgens first) and to explore their

into active metabolites.

A. Angeli et al.

404

We put forward the hypothesis crine into paracrine of the secretory

information.

products,

medium for efficient

intercellular

communication.

growth factor

sights into the mechanisms

membrane

favouring

of GCD-fluid

(EGF) (Jaspar and Franchimont,

is a

the onset

proteins,

1985) and relaxin

in type I cysts (Bradlow -.1 et al

We think, indeed, that the recently described EGF and epithelial

conditions

lesions. The significance

al., 1982), reportedly present in great amounts not be left as an open question. GCDFP-15,

release

Would this be true, BCF could be regarded as a

and hence of biochemical

of true premalignant

factors like epidermal

of endo-

fits well with the view that the fluid flowing in the ductules

mirror of the TLDU microenvironment, and/or progression

that these cells act chiefly as transducers

Their apparent polarity, which allows the intraluminal

correlations

growth

(Nardi e

1985) should

between BCF levels of

antigen

(EMA) (Collette -.* et al 1986) offer promising inwhich link biochemistry and pathology of the forms of GCD at higher

risk.

In any event, one could already say that chemical examination formed routinely

in that it offers solutions

easy definition

of pragmatic

of the cationic pattern effectively

groups; it is expected

that novel strategies

separates

of preventive

patients with GCD into major

intervention

the emerging opinion that the groups differ in risk for the subsequent will be substantiated ACKNOWLEDGEMENTS:

by large-scale

This work has been partially "Ricerca Sanitaria

will be considered, development

if

of carcinoma

follow-up.

Rome, Italy, Special Project "Oncology", .Special Project

of BCF is to be per-

value to patient care. Since now, the

supported

by the National

Contract no 85.02005.44,

Finalizzata"

no. 12/86

Research Council

(CNR),

and by the Regione Piemonte,

.

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