Gross cystic disease of the breast

Maturitus, 9 (1987) 171-181 Elsevier Scientific Publishers Ireland Ltd.

171

MAT 00424

Gross cystic disease of the breast R.B. Greenblatt

‘, V.B. Mahesh

’ and D. Sullivan

’Department of Endocrinology, Medical College of Georgia. Augusta, GA 30912, U.S.A. (Received 12 August 1986; accepted 11 May 1987) The aetiology of fibrocystic disease of the human breast remains problematical. While oestrogens may cause cystic lesions and epithelial proliferation in the mammary glands of experimental animals and certain progestogens (chlormadinone acetate and medroxyprogesterone acetate) may induce severe myoepithelial hyperplasia in beagles, the classical oral contraceptives (oestrogens and progestogens) reduce the incidence of fibrocystic breast disease in women. The role of prolactin in human breast disease is far from clear despite the fact that in rodents mammary tumors fail to develop following oestrogen administration in the absence of prolactin. Because women with gross cystic disease of the breast are at four times greater risk of developing malignant breast disease., it is felt that the administration of courses of danaxol, an impeded androgen derived from the progestin, 17a-ethinyl testosterone, has proved effective in lessening fibrocystic disease of the breast, frequently obviating the need for breast biopsy. The study of the hormonal content of fluid aspirated from gross breast cysts should help elucidate the pathophysiology of breast disease. Breast cyst fluid is rich in androgens, particularly dehydroepiandrosterone sulfate; concentrations of polypeptide hormones like FSH, LH, TSH, PRL, and calcitonin are invariably present sometimes in less and at other times in greater amounts than that found in plasma. Of particular interest is the finding of measurable levels of /I-hCG in cyst fluid but not in the serum. The question arises whether the /I-hCG is biologically active or am the assay vahtes merely the expression of radioimmunoassayable components? Preliminary (as yet unpublished) studies reveal excellent bioactivity as measured by testosterone production in Leydig cell cultures. Time will tell whether elevated levels of bioactive /I-hCG portend neoplastic potential. (Key words: Breast, Cystic disease)

Background information Many variants of the disorder commonly known as fibrocystic disease of the breast have been described. Histopathological variations in the breasts of women with fibrocystic changes vary considerably from patient to patient, in different areas of the breast, and at times in the same histological field. The term fibrocystic disease is an all-inclusive label to describe the gamut of benign disorders. Diagnosis depends on the preponderance of one component or another, i.e. stroma, ductal epithelium, glandular acini, myoepithelium, and the degree and extent of the cystic changes [ 11. As a result, a galaxy of descriptive terms are employed. Some of the synonyms in use

Correspondence to: R.B. Gmenblatt, M.D., Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, GA 30912, U.S.A. 0378-5122/87/$03.50 0 1987 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

172

Fig. 1. Chronic cystic mastitis with apocrine metaplasia.

are mazoplasia, mammary dysplasia or dystrophy, adenosis, sclerosing adenosis, adenofibroma, intracanalicular fibroadenoma, ductal papilloma and papillomatosis, mammary duct ectasia, gross cystic disease, myoepithelial hyperplasia (Reclus), and chronic cystic mastitis (Schimmelbusch) (Fig. 1). The breasts, under the influence of the endocrine glands, are in a constant state of flux, resulting in stimulatory and involutionary changes. Almost all ovulatory women after the age of 30 and those with a lactational history have mammary glands that are affected to a greater or lesser degree. The activities of the mammary gland cells often lead to the accumulation of various secretions within the lumen of ducts and acini. Frequently, the continuity of the system is interrupted and cysts are formed. Their dimensions vary greatly, from microscopic to egg-size. Gross cystic disease of the breast may be defined as the presence of a palpable, spherical fluid-filled mass. It is unusual for a cyst to be palpable by most physicians until it reaches at least 1 cm in diameter. When the breast is cut into, the cysts stand out as rounded bodies in the stroma and have a distinctly bluish tinge. They are hence, often spoken of as ‘blue domed’ cysts. These cysts are usually benign, but when the cyst fluid is bloody or mucoid, the probability of malignant change is great. The study of hormonal levels in breast cyst fluid should reflect the endocrine

173

environment within the breast itself. This is important in view of the epidemiological findings indicating that women with gross cysts have an increased risk for the development of mammary cancer [2]. There have been many measurements of various steroid levels in breast cyst fluid, but only a few studies of the peptide hormones. Srivastava et al. have shown the presence of pituitary peptides - luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL) and thyroid-stimulating hormone (TSH) - in a small number of cyst samples [ 31. Bradlow et al. also studied peptide hormones in cyst fluid and demonstrated high levels of human chorionic gonadotrophin (hCG) and PRL in cyst fluid [4]. They emphasized the fact that the radioimmunoassays for peptide hormones measured immunoreactive peptides and not necessarily biological activity. The breasts have hitherto been thought of primarily as target organs. However, concentrations of polypeptide hormones in breast cyst fluid are frequently greater than those in the serum. Such findings suggest that the glandular epithelium of the breast may be producing hormones de novo. This is further emphasized by the occurrence of /3-hCG in cyst fluid, a hormone found only in the serum and urine of pregnant women and persons harbouring a trophoblastic tumour or a neoplasm producing hCG-like hormones. The capacity for /3-hCG production by all cells in the body is probably inherent but repressed. High concentrations of /?-hCG in cyst fluid may indicate that this repression has been lessened by abnormal cellular activity [5]. Diagnosis A well-defined mass, which on needle aspiration yields a serous, discoloured or bloody fluid, confirms the presence of a cyst. Smears made from the aspirated material may suggest the benign or malignant nature of the cyst. An ill-defined lump or lumpiness, palpable only in one dimension, characterizes fibrocystic disease. Needle biopsy should be performed on any lump palpable in both dimensions and the smears obtained should be cytologically examined. A serous and greenish nipple discharge, which may be bloody, is often associated with ductal papilloma or duct ectasia. Mammography

A mammogram usually outlines quite clearly the margins of a macrocyst and at times even those of smaller cysts. Mammography is important in all women over 40 years of age because fibrocystic disease and malignancy may co-exist, so that the palpation of a definitive cystic mass, confirmed by aspiration, does not rule out a malignancy adjacent to the cystic mass. Mammography can more accurately direct where needle biopsy or aspiration should be performed. Although mammography does not always reveal an early carcinoma, it is prudent to perform it in all women with gross cystic disease. Dwmography

Thermography (CAP test) will frequently indicate the presence of proliferative activity because of excessive heat production. Women with gross cystic disease may

174

have a normal, equivocal, or abnormal thermogram. Thermography is not diagnostic, but may direct attention to a particular area of the breast. It should only be used as an extension of the physical examination. Gautherie found that in his long-term studies, 38% of women with abnormal thermograms ultimately developed breast cancer [6]. Pathophysiology

Ductal development is dependent on oestrogen stimulation, acinar and alveolar growth on oestrogen-progesterone, and galactopoieses on prolactin. Growth hormone, adrenocorticotrophic hormone ( ACTH), corticoids, insulin and androgens play facultative roles. During the follicular phase of the menstrual cycle, oestrogens induce minimal mitosis of cellular elements, but oestrogens and progesterone provoke considerable mitotic activity [7J. This is the reverse of what is encountered in the endometrium. Regressive changes, i.e. death of cells, which is known as apobiosis, is greatest at about the time of menses and may be equated with what occurs on deciduation of the endometrium. Furthermore, an important biological property of oestradiol is the induction of progesterone receptors. During the menstrual cycle, periodic changes take place in mammary tissue. Premenstrually, under the influence of sex steroids, the breast increases in size because of lobular oedema, infiltration of the perilobular stroma with fluid and plasma, and the appearance of some intra-alveolar secretory activity. During menses, a moderate intra-alveolar secretion occurs as a consequence of oestrogen-progesterone withdrawal permitting a limited milk-secretory action by prolactin. During pregnancy, extensive ductulo-lobulo-alveolar growth occurs under the influence of oestrogens, progesterone and prolactin. After delivery, with the loss of sex steroids, the presecretory alveolar epithelium is converted into active milk synthetizing and releasing cells, resulting in lactation. If milk is regularly withdrawn, the mammary epithelium continues to secrete milk. Oestrogens can antagonize the effects of prolactin on milk synthesis. Under cyclic hormonal influences, inappropriate glandular-alveolar responses may occur in the breast, particularly after 30 yr of age. The complexity of this target gland - hormonally and histologically - seems to invite discordant stimulation and involution responses, depending on the endocrine milieu, as well as many other factors. With advancing years, considerable regressive changes begin to take place and solitary or multiple cysts begin to present. Gross cystic disease occurs much more frequently after age 40 (Table I). TABLE I AGE DISTRIBUTION Years:

OF GROSS CYSTIC DISEASE (38 PATIENTS)

20-30

31-40

41-50

51-60

61+

2

4

18

11

3

175 TABLE II /?-hCG-DETERMINATION No. 33 23 16

1

IN BREAST CYST FLUID

0- < 5 mIU/ml = Negative > 5- < 20 mIU/ml= Equivocal >20-1417 mIU/ml = Positive Test’performed for LH, etc., but not /?-hCG.

73 LH = luteinizing hormone, fi-hCG = b-human chorionic gonadotrophin.

Polypeptide-like hormones in breast cyst fluid Gonadotrophin-like substances

Stimulated by the studies of Braunstein et al. [ 81, we performed radioimmunoassay measurements of the polypeptide hormones in 73 samples of cyst fluid obtained by aspiration from 38 women, of whom 32 were over 40 yr of age. It is interesting to note that more than half of the samples yielded /?-hCG values greater than 5 mIU/ml (Table II) and that in 16 cases, the values were greater than 20 mIU/ml. Serum fl-hCG values were < 5 mIU/ml in all instances when tested (Table III). FSH levels were within the normal range, while those of LH were occasionally elevated. Cytological studies were negative in all but one case, where some cells showed atypia. Thermograms did not reveal excessive heat production except in a few instances, and xeromammograms did not suggest any malignant changes. Twelve ( 12) of the 38 women had 2-4 cysts, from which cystic fluid was obtained at the same examination. It appears that each cyst independently harbours or produces peptidelike hormones at its own rate. A few examples of the variations are recorded in Table IV. In one patient with a recurrent gross cyst, very high fi-hCG values were obtained, ranging from 82 to 194 mIU/ml (Chart 1). A thermogram of her breasts was equivocal (Fig. 2), while a xeromammogram revealed cyst formation but no evidence of malignancy (Fig. 3). Biological activity in the cyst fluid from this patient was determined by injecting it into immature female mice. The positive ovarian hyperaemia test obtained suggested that the cyst fluid had hCG-like properties. The @hCG obtained from the cyst fluid in this patient was also identified by parallelism of results in dilution studies with commercial hCG in the radioimmunoassay (Fig. 4), but when it was added to Leydig cell culture no increase in testosterone concentration was observed. Prolactin (PRL)

Prolactin values were normal in cyst fluid and serum in all instances except one in which these were assayed. A markedly elevated serum level was obtained in one

176 TABLE III POLYPEPTIDE HORMONES IN WOMEN WITH MULTIPLE CYSTS (FLUID OBTAINED FROM ALL CYSTS AT THE SAME TIME) FSH

5.8 6.4

11.3 13.5

11.2 11.2

6.4 5.1

10.7 8.9

43

2.7 54.1

13.0 28.5

_ 0.4

_ _

_

45

< 5.0 5.9

_ _

-

_ _

-

_ _

_

_

-

Age

NN

43

MP BC

/?-hCG

HB

59

72.5 10.8

BR

41

22.4

CD EW

51 55

_ _ _

PRL

TSH

LH

Patient

3.9

13.9

7.2

4.0

10.8 4.8

11.4 13.7

5.8 9.4


2.5 3.8

12.3 10.9

_ 6.9

8.1 7.0

7.5 9.4 _ 10.0 9.6

BB

61

2.4 28.7 2.1

8.3 62.5 12.4

_ _

_

KL

42


24.7 _ 11.7

_ _ 11.7

_ _ _

4.0

9.6

7.0

3.0

10.1

0.9 4.5

6.5 15.8

10.4 8.2

0 0.5

11.3 _

1.9 1.5

18.0 17.0

15.2 4.6

0 0

11.0 _

DML

44

-

B-hCG = human chorionic gonadotrophin, LH = luteinizing hormone, FSH = follicle-stimulating hormone, PRL = prolactin, TSH = thyroid-stimulating hormone.

patient whose cyst was aspirated under anaesthesia. This polypeptide hormone has been incriminated in breast cancer, since PRL inhibition by bromocriptine prevents the occurrence of mammary tumours in spontaneous-tumour-bearing strains of mice [9]. Several investigators have found above-normal levels of serum PRL in women with fibrocystic disease [IO]. Others have observed a greater PRL response to thyrotrophin-releasing hormone (TRH) stimulation in women with severe fibrocystic breast disease [ 1I]. We and others have not been able to corroborate these findings, although in our series occasional women with severe fibrocystic disease did indeed have mildly elevated levels of serum PRL (Chart 2).

177 TABLE IV COMPARISON OF POLYPEPTIDE HORMONE THREE REPRESENTATIVE CASES Patient

Age

AH

53

EG

53

DMcL

44

LEVELS IN BLOOD AND CYST FLUID IN

/?-hCG

LH

FSH

Serum Cyst fluid

<5.0 194.0

5.7 46.7

10.2 7.8

7.9 a.4

2.0 1.8

Cyst fluid

<5.0 11.0

7.3 11.0

11.2 5.6

13.3 5.2

4.5 11.5

<5.0 <5.0

7.9 6.5

22.8 10.4

312.0’
4.9 11.3

;suid

PRL

TSH

’ Blood taken during anaesthesia (stress raises prolactin levels). Serum /?-hCG levels in all cases < 5.0. TSH levels in cyst fluid higher than in serum in almost every instance. FSH usually higher in serum than cyst fluid. B-hCG = b-human chorionic gonadotrophin, LH = luteinizing hormone, FSH = follicle-stimulating hormone, PRL = prolactin, TSH = thyroid-stimulating hormone.

Thyroid-stimulating hormone (TSH) We found TSH values in cyst fluid to be greater than those in serum in almost every instance tested and to be above-normal in the majority of cases. For years there have been claims that fibrocystic disease occurs with greatqfrequency in. women with poor thyroid function [ 121. It has also been contended that breast cancer may be related to real or subclinical hypothyroidism. In any event, there are advocates of thyroid

200

g

1

Serum /3hCGcS mlU

150-

E s

loo-

d u 5 I,

50-

0

’

1 719131

I

I

I

I

I

I

I

I

11130131

Q/14/32

2117133

3ilOl33

7114/33

l/10/34

6/lSIM

llH5l3.4

Date of Cyst Fluid Aspiration Chart 1. B-hCG and LH content in breast cyst fluid in a woman 53 yr of age. (Serum PRL levels were moderately elevated in 2 of the 12 patients before danazol treatment.)

178

Fig. 2. Abnormal thermogram in a 53-yr-old woman (AH) with very high /?-hCG levels in aspirated cyst fluid (B-hCG = B human chorionic gonadotrophin).

hormones and iodine preparations for the treatment of benign breast disease. Peters et al. found many regimens that offered relief in the treatment of painful mastopathy, among them being thyroid hormone [ 131. Management

Aspiration, if thoroughly performed, results in the elimination of the cyst in the majority of cases. Gorins and his colleagues obtained cures in 95% of cases provided that, after aspiration of the cysts, a compression velpeau bandage of the chest was applied for several days [ 141. For those unresponsive to such manoeuvres, hormonal therapy is indicated. Danazol and bromocriptine have been employed with much

Fig. 3. Xeromammogram

(AH). Arrows point to cystic mass which has been aspirated repeatedly.

success, particularly in patients with microcystic disease. Progestogens as often aggravate as improve the condition. Surgery should be limited to those cases where the cyst fluid is mucoid or bloody, where cytology reveals suspicious cells, or where mammography and history indicate an unusual risk. Conclusions There is considerable ongoing research on the endocrinology of gross cystic disease of the breast. The reported risk factor for developing breast cancer in sufferers from gross cystic disease is said to be four times that in the normal woman, Will high levels of /I-hCG prove to be a warning signal, especially if thermography reveals abnormal heat production? The possibility of a link between specific hormones in cyst fluid and

03

1 0.8

0.7

0.6

0.5 8 m' II

0.3

0.2

0.1 1

0.0

.I, 10

20

hCG CONCENTRATION

50

100

200

(mlU/ml)

Fig. 4. Radioimmunoassays of cyst fluid paralleled commercial hCG in dilution studies (B-hCG = human chorionic gonadotrophin).

B&3

Afier

Chart 2. Serum prolactin levels in 12 patients with fibrocystic breast disease before and after danazol treatment. (Serum PRL levels were moderately elevated in 2 of the 12 patients before danazol treatment.)

181

the occurrence of breast cancer is being explored. The surprising finding in our study, aside from the frequency of elevated levels of /I-hCG, was that the TSH levels in cyst fluid were in every instance greater or about equal to those in serum. But more impressive is the fact that the values in cyst fluid were usually above normal. Although of great interest, the significance of such findings must for the present remain a matter for speculation. Acknowledgement Funds to support this work were provided by the Southeastern Research Foundation. References 1 Greenblatt RB, Cbaddha JS, Teran A-Z et al. Fibrocystic breast disease: pathophysiology, hormonology, treatment. Contemp Surg 1984; 24: 49. 2 Haagenson CD. Diseases of the breast. Philadelphia, WB Saunders, 1971. 3 Srivastava LS, Pescovitx SJ, Sit@ RD et al. Radioimmunoassay of some hormones simultaneously measured in serum and breast cyst fluid. Experimentia 1977; 33: 1659. 4 Bradlow HL, Schwartz MK, Fleisher M et al. Hormone levels in human breast cyst fluid. In: Angeli A, Bradlow HL, Dogliotti L, eds. Endocrinology of cystic breast disease. New York, Raven Press, 1983; 59. 5 Vaitukaitis JL, Ross GT, Braunstein GD et al. Gonadotropins and their subunits: basic and clinical studies. Recent Prog Horm Res 1976; 32: 289. 6 Gautherie M, Gros CM. Breast thermography and cancer risk prediction. Cancer 1980; 45: 51. 7 Ferguson DJP, Anderson TJ. Morphological evaluation of cell turnover in relation to the menstrual cycle in the “resting” human breast. Br J Cancer 1981; 44: 177. 8 Braunstein J, Vaitukaitis J, Carbone P et al. Ectopic production of human chorionic gonadotropin by neoplasia. Ann Intern Med 1973; 78: 39. 9 Welsch C, Meites J. Prolactin and mammary carcinogenesis. In: Sharma RK, Criss WF, eds. Endocrine control in neoplasia. New York, Raven Press, 1978. 10 Cole EN, Sellwood RA, England PC et al. Serum prolactin concentrations in benign breast disease throughout the menstrual cycle. Eur J Cancer 1977; 13: 597. 11 Geller S, Scholler R, Rouanet-Rousseaux F et al. Exploration hormonale des mastopathies b&ignes par le tesf combine au LH-RH + TRH, confrontation avec les don&es de la ttlethermographie. Mediterr M&d 1977; 141: 79. 12 Daro AF, Collin HA, Samos FH. The effect of thyroid on cystic mastitis. J Int Co11Surg 1964; 41: 58. 13 Peters F, Pickardt CR, Breckwoldt M. Hormonal status of women with benign cystic breast disease: clinical implications. In: Angeli A, Bradlow HL, Dogliotti L. eds. Endocrinology of cystic breast disease. New York, Raven Press, 1983; 113. 14 Gorins A, Netter A, Tournant B et al. Les kystes mammaires. In: Netter A, Gorins A, eds. Actualites gynecologiques, Paris, Masson, 1984.