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Diagnosis and Treatment of Premalignant Lesions of the Breast
DIAGNOSIS AND TREATMENT OF PREMALIGNANT LESIONS OF THE BREAST MURRAY M. COPELAND, M.D., F.A.C.S. CHARLES F. GESCHIGKTER, M.D.
* AND
t
THE following benign breast entities are considered to have a higher incidence of malignant potentiality associated with them than is noted in the breasts of women in the general population not so affected:
1. 2. 3. 4. 5. 6. 7.
Virginal hypertrophy and excessive mammary development Residual lactation mastitis Aberrant mammary tissue Fibroadenoma in pregnancy and at the menopause Intracystic papilloma Mammary dysplasia (chronic cystic mastitis) Keratoses of the nipple; retraction of the nipple; the bleeding nipple
A survey of diagnostic findings and treatment of this group will be given, pointing out the incidence of carcinoma or sarcoma involved, and emphasizing the prognosis before and after malignant changes have occurred. VIRGINAL HYPERTROPHY AND EXCESSIVE MAMMARY DEVELOPMENT
Excessive and persistent enlargement in one or both breasts in the female may occur during adolescence (Fig. 490 and 491) or pregnancy. The cause of the hypertrophy is unknown. Either one or both breasts may be affected. Both epithelium and connective tissue take part in the enlargement (Fig. 492). Growth is progressive for a period of months but rarely extends beyond one or two years' duration. During the period of enlargement, cancer has never been observed but previously hypertrophied breasts have a higher incidence of mammary carcinoma than those of normal size. In our series of twenty-four cases of virginal hypertrophy, two patients subsequently developed mammary carcinoma seventeen to twenty years after the onset of the enlargement. In a study of 1400 cases of infiltrating mammary carcinomas which had complete clinical histories recorded, sixteen patients gave a history of virginal From the Departments of Oncology and Pathology, Georgetown University Medical Center, Washington, D. C. * Professor of Oncology and Director of the Department of Oncology, Georgetown University Medical Center; Attending Surgeon in Oncology, Georgetown University Hospital and Gallinger Municipal Hospital (Georgetown Division). t Professor of Pathology and Director of Department of Pathology, Georgetown University Medical Center; Pathologist-in-Chief, Gallinger Municipal Hospital.
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MURRAY M. COPELAND, CHARLES F. GESCHICKTER
hy 1
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Fig. 490. Bilateral virginal hypertrophy in a girl 17 years of age.
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Fig. 491. Gross specimen of breast removed for benign virginal hypertrophy. Notice the bulky dense structure of the tumor without evidence of loose areolar tissue or fat and the absence of cystic changes.
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hypertrophy. The incidence of cancer, therefore, seems to vary between 1 and 2 per cent. The treatment of virginal hypertrophy is limited to surgery. Plastic procedures are to be carried out in the least bulky breasts. Simple amputation is the treatment of choice in the large congested and painful forms of virginal hypertrophy. In those breasts where the slightest suspicion of cancer exists, exploration is indicated. If malignant change has supervened (usually after many years), radical mastectomy is the necessary treatment. In the male, gynecomastia also increases the susceptibility to carcinoma. Menville found two reports in the literature of malignant change in
Fig. 492. Microphotograph showing hypertrophy of periductal and intralobular tissue in virginal hypertrophy. Lobule formation is minimal.
gynecomastia. Gilbert, in a study of forty-seven patients with cancer of the male breast, found that nine cases were associated with pre-existing or existing gynecomastia. Gynecomastia presents a variety of clinical pictures, the recognition of which is important from the standpoint of prognosis and treatment. The diffuse hypertrophic form seen in early puberty (Fig. 493) often subsides spontaneously or yields to testosterone therapy in the form of testosterone propionate 25 mg., given twice weekly for twelve weeks. In the more chronic fibroadenomatous type it must be carefully distinguished from carcinoma of the male breast (Fig. 494). The rarest form of gynecomastia is that of true feminization of the breast.
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Surgical excision is indicated for any breast with gynecomastia if any doubt exists as to the diagnosis and, should frozen sections reveal cancer, a radical mastectomy should be performed. RESIDUAL LACTATION MASTITIS
The duration of. symptoms in chronic lactation mastitis ranges from two months to twenty-eight years. The differential diagnosis between
Fig. 493. A photograph of gynecomastia occurring in a Negro boy of 18 years. Cross section of the enlargement is shown below. This form often recedes spontaneously. (After Geschickter, C. F.: Diseases of the Breasts, J. B. Lippincott Co. , Philadelphia, 1945.)
cancer and residual lactation mastitis may be extremely difficult. In eleven of thirty-six patients without frank pus, the inflammatory nature of the lesion was indicated by heat and redness in the overlying skin and by the systemic response of the patients. In the remaining twentyfive cases the area of mastitis was described as a definite mass or nodule. In nineteen of these patients an erroneous diagnosis of malignancy was made, either on the basis of the clinical findings or upon microscopic examination. The long time elapsing after the last lactation, together with the absence of reddening or suppuration, made the diagnosis diffi-
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cult in this group of cases. At exploration, the microscopic examination shows residual lactation in some of intact lobules, areas of inflammatory changes and periductal accumulations of wandering cells. The lining cells of ducts are increased in number and are undergoing desquamation. In areas, little remains but a few acini or tubular structures, some of which are partly destroyed, embedded in fibrous tissue (Figs. 495 and 496). McDonald found that in women with cancer of the breast who had
Fig. 494. Microscopic section of a more chronic type of fibroadenomatous gynecomastia. Note the proliferation of the duct epithelium. Such lesions when of long standing may show malignant changes and must be carefully distinguished from carcinoma.
borne children, 42 per cent had had abnormal lactation compared with 20 per cent in the control group. Wainwright had previously found a similar incidence.. in his study. Among 1260 cases of infiltrating mammary cancer occurring in parous women, seventy-eight (or 6 per cent) gave a history of lactation mastitis with or without abscess formation: In only thirty-eight (or 3 per cent) of these patients, however, was the cancer related definitely to the scar or the residual lump. From these thirty-eight cases the following observations on cancer in lactation mastitis are made. The interval be-
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tween mastitis and the appearance of mammary cancer averaged twentyone years. Age distribution extended from 39 to 67 years. The onset of the malignant growth was related to rapid enlargement of a pre-existing lump, to the development of a mass beneath a scar, to the appearance
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4 Fig. 495. Upper, Gross specimen with nipple attached showing extent of changes associated with residual lactation mastitis. Lower, Cross section of gross specimen showing the large firm indurated mass, leaving doubt as to the diagnosis unless microscopic sections are studied.
of tenderness in the quiescent lesion, or to changes in the overlying skin. The symptoms referable to the supervening malignant change were usually of short" duration as the growth progressed rapidly. Among our cases the prognosis was worse than in those cases of cancer arising during pregnancy or during active lactation. All patients were treated by radical
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mastectomy except one on whom a palliative simple mastectomy was performed. No patient was cured, though one individual lived eight years after radical mastectomy and then died of metastases.
Fig. 496. Microscopic section of residual lactation mastitis. Inflammatory changes are present. The duct and lobule regions show periductal accumulation of wandering cells. Lining cells in some areas may be increased in number and undergo desquamation. Cancer has been found developing in such areas in thirtyeight instances from a series of seventy-eight patients who gave a history of residual lactation mastitis of the chronic type with or without previous abscess formation. .
ABERRANT MAMMARY TISSUE
A distinction must be drawn between supernumerary breasts (Fig. 497, A) which have either nipple or areola (or both), in combination
with persistent or atrophic gland tissue, and aberrant breast tissue which is without nipple or areola (Fig. 497 B). In the older literature the statement is frequently found that tumor formation is relatively more common in the supernumerary breast than in the normal organ. Spcert and also de Cholnoky, in reviewing the subject, indicate that the evidence of greater frequency of cancer in the supernumerary breasts is lacking. There is evidence, however, that aberrant axillary mammary tissue (not supernumerary breasts) is more prone to malignant change than normal breast parenchyma (Matti, Razemon and Bizard, Biancheri). The most common tumors found in aberrant breast tissue are fibroadenoma and
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carcinoma. Carcinoma is more frequent than benign tumor formation in aberrant mammary tissue. It is usually found only in proximity to the normal breast, that is, in the axillary, sternal or clavicular regions. In our series there have been seven axillary aberrant breast cancers and two such lesions were situated along the sternum.
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Fig. 497. A, Photograph of female patient with a supernumerary nipple and breast at the base of the right axilla. B, Photograph of a male patient with aberrant breast tissue and without a nipple in the right axillary region.
The symptoms included swelling, tenderness and pain or discomfort in using the arm. These findings existed from four to twenty-four months before treatment was instituted. Where cancer existed, the tumors varied from 2 to 8 em. in diameter. In the axilla the tumor was surrounded by fat or indurated tissue. In addition, many involved lymph nodes were seen in the majority of cases. The prognosis is exceedingly poor where cancer is found. Only one patient lived beyond the five-year period, dying ultimately of metastases. The treatment for aberrant mammary tissue consists of exploration for diagnosis, followed by radical mastectomy when cancer is found. Excision is indicated when any tumor formation is present in supernumerary breasts (Fig. 498). All aberrant breast nodules at the periphery of
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the breast, especially in the axilla or along the sternum, must be held suspect until proved otherwise. Experience, of course, has shown that primary axillary cancer may extend into the mammary gland and, also, that a minute primary breast cancer escaping detection may be responsible for an axillary growth.
Fig. 498. Microscopic section from localized hypertrophy found in a supernumerary breast. Note the duct and lobule lining cell proliferation. Such areas occasionally give rise to carcinomatous change, and are more often seen in aberrant breast tissue not related to supernumerary breast with nipple formation.
FIBROADENOMA IN PREGNANCY AND AT THE MENOPAUSE
The rapid growth of fibroadenoma in pregnancy and the various morphological changes that occur in these tumors during lactation have been described by us in detail elsewhere. Enlargement is more rapid during the first half of pregnancy than during the second. Increase in size late in pregnancy usually results from secretory changes. Most often there is rapid onset in growth of a pre-existing firm, circumscribed breast nodule; multiple growths may be present. The tumor must be differentiated from cancer, cystic disease or some other rare, firm lesion of the breast. The lack of retraction of the nipple or of atrophy of the skin, together with the average age incidence, are helpful points in diagnosis. The tumors are composed of a growth of ducts and an abundance of periductal connective tissue. The rapid growth and the variety of bizarre microscopic changes which the fibroadenoma may undergo in response to hormonal influences of gestation and lactation may lead to
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Fig. 499. A photomicrograph of lactating changes in fibroadenoma showing areas of hyalinized fibrous tissue, dilated ducts and lobular acini. The hyalinized stroma is sometimes cellular and resembles sarcoma.
s
Fig. 500. A microphotograph of lactating fibroadenoma with development of early carcinoma. Note the proliferating carcinoma with acinar arrangement of cells.
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difficulties in diagnosis and arouse suspicion of malignant change (Figs. 499 and 500). Fortunately, however, we have observed cancer developing in lactating fibroadenoma only twice in forty-four patients. Prompt excision of fibroadenomas is indicated, particularly during the child-bearing period, in order to avoid the difficulties in diagnosis and treatment associated with rapidly enlarging tumors in pregnancy and lactation. There is general agreement that mammary cancer developing during pregnancy or lactation is unfavorably influenced. During pregnancy the malignant change in fibroadenoma is a carcinomatous one (Fig. 500). However, malignant changes occur in these
Fig. 501. Patient with giant mammary myxoma showing a great increase in size of the breast which is nodular, firm and with evidence of ulceration.
benign lesions under other conditions. Toward the menopause, giant myxoma may develop in fibroadenoma, slowly growing over a period of five or six years with rapid enlargement toward the end (Fig. 501). This type of menopausal giant mammary myxoma was first described by Johannes Muller in 1836. The tumors are large, with great cystic spaces into which fibrous polypoid masses project. These masses are made up of myxomatous connective tissue in polypoid fibrous structures covered by cuboidal epithelium as seen under the microscope (Fig. 502). There is a definite incidence of sarcoma in this group. The differentiation between giant myxoma and fibrosarcoma is not easy and requires careful microscopic study and experience in some cases. If sarcomatous change
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MURRAY M. COP·ELAND, CHARLES F. GESCHICKTER
is found, amputation of the breast including the pectoral fascia, without axillary dissection, is indicated. The lesions do not as a rule metastasize to regional lymph nodes. Wide local excision is indicated for the benign lesions. Pasternack and Wirth collected thirty-one cases of large fibroadenomas from the literature in which the lining epithelium of ducts or cysts underwent squamous cell metaplasia. Oliver reported three cases among 600 instances of fibroadenoma. The authors have observed such changes in an additional three cases, making a total of thirty-seven lesions. with squamous cell metaplasia. Such a finding is more common in giant mam-
n n
tis mic Fig. 502. High power photomicrograph of giant myxoma showing marked hypertrophy of periductal fibrous tissue with polypoid masses projecting into cystic spaces covered by cuboidal epithelium. This lesion is secondary to pre-existing fibroadenoma.
mary myxoma than in ordinary fibroadenoma. From among the thirtyseven cases with squamous metaplasia, six instances of squamous cell carcinoma have been recorded (Foot and Moore, Haagensen, Pasternack and Wirth, Geschickter). Squamous cell metaplasia is a rare finding in fibroadenoma, but cancer developing in squamous cell metaplasia found in fibroadenoma is not rare. Should squamous carcinoma be found in a fibroadenoma or giant myxoma, radical mastectomy should be performed.
T in san exi and opa pres or A from 503 the
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INTRACYSTIC PAPILLOMA
Benign intracystic papilloma includes (1) papillary invaginations of the larger ducts; (2) intracystic papillomas; and (3) papillary hyperplasia which occurs in adenosis of the breast. The condition, with the exception of papillary changes seen in patients with adenosis of the breast, which will be ,considered elsewhere, occurs usually in women near, at, or beyond the menopause. It occurs with equal frequency in nulliparous and in parous women.
Fig. 503. Intracystic papilloma. Drawing shows proliferation of adenomatous tissue at base of the cyst and beginning infiltration of the cyst wall. There was microscopic evidence of malignant change.
The tumors vary from one to several centimeters in size, occur usually in the central zone of the breast and are frequently associated with a sanguineous discharge from the nipple. Evidence of a lump may have existed for from six months to five years. The mass is soft, compressible and usually freely movable; it is shown on transillumination to be an opaque area; and causes bloody discharge from the nipple when compressed. The tumor has at times been referred to as a low grade papillary or duct cancer (Gray and Wood). Although the authors believe that it is possible to distinguish benign from malignant papillomas of the breast on pathological grounds (Figs. 503 and 504), it must be pointed out that in 17 per cent of our cases the lesions were multiple and approximately 5 per cent were bilateral. 7·
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Where simple excision was the treatment used in forty-eight cases followed by us, eight had further operations with subsequent papillomas and three had radical mastectomies for papillary cystadenocarcinoma. This type of benign tumor is also capable of giving rise to a gelatinous carcinoma. When simple excision for intracystic papilloma is done, recurrence can be expected in around 20 per cent of patients so treated. Six to 8 per cent of the recurrences will be in the form of malignant change. The
Fig. 504. Photomicrograph of malignant papilloma occurring in the wall of a large cyst. Stalks and cyst walls of such lesions must be carefully studied microscopically for evidence of malignant change and infiltration of surrounding breast tissue.
majority of recurrences of intracystic papilloma are due to the fact that this condition may affect the duct system diffusely or bilaterally and at the time of excision the clinician is only aware of the lesion presenting symptoms. MAMMARY DYSPLASIA
More than a hundred years ago Sir Benjamin Brodie recognized the cystic form of mammary dysplasia as a benign condition of the breast
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and .observed that it was more common in unmarried and childless women (average 35 years). All forms of mammary dysplasia follow this rule and it is, therefore, a disease of increasing incidence in women of the American population. Mastodynia. Of the three forms of mammary dysplasia, simple mammary nodosity with pain is the most common and least serious. It is common in women between the ages of 20 and 40 years. Married women predominate in a ratio of 3 to 1. It is characterized by discomfort, gradual in onset over a period of months, worse in the premenstruum and referred to a portion of one or both breasts (usually upper and outer third), which is more tender, firmer and thicker than the surrounding breast. The defective lobule formation, as demonstrated in recent studies, is due to reduced function of the corpus luteum. Normal lobule formation is dependent on the proper ratio of estrogen and luteal hormones. The authors have followed 310 cases of mastodynia for more than five years before observing a single case of mammary carcinoma associated with this form of dysplasia. This married patient had mastodynia fifteen years before showing evidence of cancer. She had gone through a normal pregnancy twelve years prior to developing the malignant lesion and had been free of the mastodynia since that time. The cancer developed in aberrant breast, apparently unrelated to the previous mastodynia. The treatment of mastodynia is varied. Once the diagnosis of cancer or true infection has been ruled out, simple supportive measures are worthwhile, including reassurance and a breast support (brassiere). Estrogen has proved effective in controlling the condition. Testosterone pro. pionate in doses of 25 mg. per week for a short while has proved satisfactory in a few cases, but progesterone therapy is the treatment of ·choice. Patients have shown improvement when progesterone has been administered in 5 mg. doses hypodermically twice a week for the last two weeks of one or two consecutive cycles with an effective total dose ranging between 20 to 40 mg., two or more years having elapsed after endocrine therapy without recurrence of symptoms. . Cystic Disease. Cystic disease is the next most common form of mammary dysplasia. Women at or near the menopause formthe largest group of patients, usually between the ages of 41 and 45 years. Childless women predominate in the ratio of 3 to 2. One of us (C. F. G.) has found evidence to support the probability that an intense or unopposed estrogenic stimulus results in the formation of the cysts. The symptoms of cystic disease usually appear either abruptly or exist for a relatively short time (days or weeks). The chief complaint is the discovery of a lump. Mild pain, soreness and a burning or sticking sen-
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p t i t B A .\ specimen of a large cyst (blue-domed) B Fig. 505. A, Photograph of gross occurring in a patient aged 45 years. B, Photograph of cross section of the wall (blucyst ·d m d ) occurshowing smooth lining without evidence of papillomatous formation. lion of Lhc .y -L wall u ' formati n.
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Fig. 506. Microphotograph of cysts of the breast with typical cuboidal cell lining. The neighboring ducts are dilated. The cysts are filled with coagulated secretion.
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sation, prior to the appearance of the cystic lump, are occasionally observed. The breasts are usually fairly large or adipose and the cysts are found proximal to the breast periphery. The tumor is round, smooth, tense and freely movable and frequently fluctuates. Cysts may change in size and tend to. disappear in about 7 per cent of the cases. In a large number of patients only one cyst of appreciable size is found, but single cysts may be found in both breasts (11 per cent). Multiple cysts are found in one or both breasts in 25 per cent of cases at the first examination. They occur in a slightly younger age group and the symptoms are similar to those associated with adenosis. The cysts usually can be transilluminated. The majority of them are easily aspirated, yielding a cloudy or a serous fluid. A thick, fibrous, walled cyst deep in the breast makes diagnosis difficult and, if aspiration is unsuccessful, exploration should be resorted to. The treatment of choice is excision of single cysts (84 per cent of the patients are free from further complaints). In 15 per cent of the patients other cysts develop in the breast. Aspiration may be employed if the breasts are carefully watched subsequently. Recurrent tumors of the breast in patients past the menopause must be accurately diagnosed. The mammary cyst appears as a tense, bluish, walled cyst embedded in dense, fibrous stroma (Fig. 505). Multiple small cysts and dilated ducts may be seen in the surrounding tissue. Lobule structure is poor. The lining epithelium of the cyst is often replaced by fibrous tissue, or the persistent cuboidal epithelium contains eosin-staining cytoplasm (Fig. 506). Cancer cysts and intracystic papillomas are not the result of this process. The authors have followed for more than five years 445 patients with cystic disease treated by simple excision or exploration and have observed five cases of associated mammary cancer. This agrees with other observations in the literature (Warren) that it is twice the expected rate. It is still low enough, however, to make conservative procedures the treatment of choice. Adenosis of the Breast. This is, fortunately, the least common form of mammary dysplasia, since it is the most serious in many of its aspects. Adenosis (Schimmelbusch's disease) is most frequently observed in women between the ages of 35 and 44 years. It is characterized by the occurrence, in one or both breasts, of multiple nodules which measure from Imm. to 1 cm. in diameter and are fusually distributed about the upper and outer hemisphere (Fig. 507). In one-third of the patients pain is a conspicuous feature. The breasts, as in mastodynia, are thickened, granular and tender with the addition of multiple nodules. An edge can be palpated at the periphery of the diseased portion. This "caking" or induration may at times suggest cancer.
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MURRAY M. COPELAND, CHARLES F. GESCHICKTER
The pathologic process may be limited or diffuse in one breast or in both. Throughout the breast parenchyma, increased periductal and perilobular fibrous tissue, small cysts, minute adenomas, papillomas and dilated ducts are characteristic (Fig. 508). In advanced cases, intraductal hyperplasia and the epithelial proliferation of acini closely resemble changes seen in various forms of cancer. The patients fall into two endocrine groups: (1) patients in early sexual maturity with small breasts due to stunting from high estrogenic
a
Fig. 507. Drawing of cross section of a breast with typical changes in adenosis (Schimmelbusch's disease). Note the cystic areas and small nodulations made up of adenomatous and papillary tissue. In the base of the breast beneath the nipple there is noted a solid area revealing malignant change developing within an adenomatous area.
stimulation in adolescence (C. F. G.); (2) patients of 30 years of age or more, who have characteristic changes in the breast of one or more year's duration, due to prolonged moderate hyperestrinism (C. F. G.) with pain and menstrual complaints and, usually, psychically upset. These symptoms are common in both groups. While the changes seen in mammary dysplasia are not essential to the development of mammary cancer, they do represent changes due to hyperestrinism which, experimentally, leads to the development of breast cancer in animals. Clinically, we have found that among 150 pa-
of
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Fig. 508. Photomicrograph of adenosis of breast showing intracystic papillomas and nonencapsulated epithelial proliferation of the lobules.
Fig. 509. Photomicrograph of cystic adenocarcinoma developing in adenosis of the breast.
tients with adenosis of the breast who were carefully followed, the incidence of cancer was 4 per cent (5 cases), while among those with cystic
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MURRAY M. COPELAND, CHARLES F. GESCHICKTER
disease, the incidence was 0.79 per cent. The incidence of breast cancer among women as a whole is 0.42 per cent. Therapy in adenosis consists of surgical investigation of all doubtful nodules (Fig. 507). Biopsies which show cancer (Fig, 509) indicate a radical mastectomy. Estrogenic therapy is not satisfactory in adenosis and is unsafe to use. Aspiration of cysts may be indicated to obliterate them. Progesterone for symptomatic relief, administered in 10 mg. doses hypodermically twice a week, giving from 40 to 120 mg. as a total dose between two or three menstrual cycles, is the treatment of choice. Recurrence of discomfort may be persistent or again encountered after two or more years. RETRACTION OF THE NIPPLE; KERATOStS OF THE NIPPLE; THE BLEEDING NIPPLE
Congenital retraction of the nipple, nonpuerperal serous discharge from the nipple and postlactation milky discharge from the nipple (galactorrhea) do not predispose to cancer of the breast or nipple, in our experience. On the other hand, keratotic lesions of the nipple or areola may represent the early stages of cancer or constitute a precancerous lesion. Intermittent retraction of the nipple or acquired retraction of the nipple may be a symptom of carcinoma already present, although the retraction cannot be classified as having any bearing on the etiology of the disease. Paget's cancer of the nipple, which ultimately results in ulceration of this organ and the formation of a palpable tumor in the breast beneath, is one of the more malignant forms of mammary carcinoma. A number of lesions of the nipple must be differentiated from this disease and some of these must be looked upon as early stages or premalignant phases of this form of carcinoma. As a rule, Paget's cancer is preceded by either a red, granular nipple, by a shallow ulceration or fissure, or by a scaly keratotic lesion which ultimately weeps and ulcerates. The earliest stages of the tumor may arise in the ampulla and, in this location, the premalignant phases cannot be clinically observed. The persistent keratotic, cr~cked or irritated nipple must, therefore, be biopsiedin order to determine the earliest phase of the disease. In Paget's carcinoma of the nipple, the underlying ductal system is involved in nearly every case and a radical mastectomy is essential for cure (Figs. 510, 511 and 512). In cases in which the nipple is widely excised, with postoperative breast irradiation, recurrence and axillary metastases are the rule. Fifty cases of Paget's cancer, with or without palpable tumor in the breast parenchyma, have been traced and, of this number, twenty-four (48 per cent) survived the five-year period. Keratoses, fissures, ulcerations and red, granular changes in the nipple
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Fig. 510. Gross specimen of Paget's disease of the breast with typical Paget's cancer of the skin and associated transitional carcinoma of the underlying ducts. hr('[ t \\ i h t 'pit'aI Pug it iOIl tI (·Uf(·iIlOIllU of t h(' \llld .r1 ·illg dll(:
Fig. 511. Microphotograph of Paget's carcinoma involving the skin of the ni pple and areola.. Note the typical pagetoid cells in the tumor.
should be treated by excision of the nipple, with a margin of skin and a core of underlying ducts and fatty tissue, if the lesion fails to heal
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MURRAY M. COPELAND, CHARLES F. GESCHICKTER
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Fig. 512. Microphotograph of ducts beneath the nipple showing proliferation of tumor cells (transitional cell carcinoma), some of which are forming new ducts.
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B
B B . Fig. 513. Patient with bilateral keratotic changes of the nipples. The nipples are encrusted and there is edema of the surrounding areola. · Th nipp\
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within three to four weeks after cleansing and protective measures. If cancer is found, radical mastectomy is indicated. If cancer is not found; local excision will suffice. The most definite precancerous lesion of the nipple is the scaly keratotic area that fails to heal when washed daily with soap and water followed by alcohol and protected with simple bland ointment, such as petrolatum (Fig. 513). Such a keratotic area can be differentiated from true eczema which usually involves the areola as well as the nipple and other portions of the body, including the ears and the flexor surfaces of the extremities. The incidence of benign and malignant keratotic lesions of the nipple can be judged from the following experience of the authors. During the same period in which seventy-two cases of Paget's cancer were observed, fifty-two patients with benign keratosis, some of which were complicated .by ulceration, were treated. Intracystic papilloma of the ampulla of the nipple, with malignant change, also occurs and, occasionally, is bilateral. The prognosis is better than in Paget's cancer. More rarely, sweat gland cancer, or ordinary basal or squamous cell cancer, is observed in the areola and has a better prognosis than Paget's cancer. A serological test for syphilis should always be performed before surgery. Chancre of the nipple may simulate the disease under discussion. Sanguineous discharge from the nipple may be a symptom of cancer already present or, more frequently, 'accompanies a benign intracystic papilloma which is a premalignant lesion. Fourteen per cent of all mammary carcinomas will be accompanied by a sanguineous discharge from the nipple at the time of clinical examination. However, in only 4 per cent of all breasts examined is a sanguineous discharge the earliest sign of cancer. Fifty per cent of all intracystic papillomas will give a history of sanguineous discharge (a precancerous lesion). In Schimmelbusch's disease (adenosis) sanguineous discharge from the breast is noted in 4 per cent of the cases (a precancerous lesion). The practical point of the matter is that a sanguineous discharge from the breast nipple is an indication of a malignant or premalignant lesion until proved otherwise by surgical exploration. REFERENCES Biancheri, T.: Carcinoma in aNode of Aberrant Accessory Mammary Tissue. Pathologica 24:401,1932. Bloodgood, J. C.: Paget's Disease of the Female Nipple. Arch. Surg. 8:461, 1924. Bloodgood, J. C.: The Treatment of Tumors of the Breast During Pregnancy . and Lactation. Arch. Surg. 18:2079, 1929. Bloodgood, J. C.: Borderline Breast Tumors. Am. J. Cancer 16:103, 1932. Brodie, B.: Sero-cystic Tumors of the Breast. Clin. Lectures on Surgery, Lecture 24:206, 1846. Bronstein, I. P.: Gynecomastia. Endocrinology 24:274, 1939.
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-MURRAY M. COPELAND, CHARLES F. GESCHICKTER
Cheatle, G. L. and Cutler, M.: Tumors of the Breast. London, Edward Arnold & Co., 1931, p. 142. de Cholnoky, T.: Supernumerary Breast. Arch.Surg. 39:926, 1939. Cohn, L. C.: Paget's Disease of the Female Breast. Arch. Surge 34:201;1937. Copeland, M. M.: Newer Aspects of Benign Tumors of the Breast. Arch. Surge 55:590, 1947. Copeland, M. M.: Benign Tumors of the Breast and Associated Conditions. S. Dakota J. Med. & Pharm. 2:116, 1948. Cutler, M.: Benign Lesions of the Female Breast Simulating Cancer. J.A.M.A. 101:1217, 1933. Delannoy, E. and Driessens, J.: Sudoriparous Type of Epithelioma of the Breast. Echo Med. du Nord 4:169, 1935. Fisher, G. A., SchoufHer, G. C., Gurney, G. E. and Benshadler, G. H.: Massive Breast Hypertrophy. West. J. Surge 51:349,1943. Foot, N. C. and Moore, S. W.: A Fatal Case of Deep-seated Epidermoid Carcinoma of the Breast with Widespread Metastases. Am. J. Cancer 34:226, 1938. Fox, S. L.: Sarcoma of the Breast. Ann. Surge 100:401, 1934. Gesehickter , C. F., Lewis, D. and Hartman, C. G.: Tumors of the Breast Related to the Oestrin Hormone. Am. J. Cancer 21:828, 1934. Geschickter, C. F. and Lewis, D. D.: Pregnancy and Lactation Changes in Fibroadenoma of the Breast. Brit. M. J. 1:4026, 1938. Geschickter, C. F.: Corpus Luteum Studies. III. Progesterone Therapy in Chronic Cystic Mastitis. Clin. Endocrinol. 1:147, 1941. Geschickter, C. F.: Diseases of the Breast. Philadelphia, J. B. Lippincott Co., 1945. Gilbert, J. B.: Carcinoma of the Male Breast with Special Reference to Etiology. Surg., Gynec. & Obst. 57:451, 1933. Gilbert, J. B.: Pathologic Physiology of Malignant Tumors of the Testis Associated with Breast Hyperplasia. Arch. Surge To be published. Gray, H. K. and Wood, G. A.: Significance of Mammary Discharge in Cases of Papilloma of the Breast. Arch. Surge 42:203, 1941. Haagensen, C. D.: The Bases for the Histologic Grading of Carcinoma of the Breast. Am. J. Cancer 19:285,1933. Harrington, S. W.: Carcinoma of the Breast: Results of Surgical Treatment When the Carcinoma Occurred in the Course of Pregnancy or Lactation and When Pregnancy Occurred Subsequent to Operation (1910-1933). Ann. Surge 106:690, 1937. Hoffman, W. J.: Hormone Therapy of Male Breast Hypertrophy. Am. J. Cancer 36:247,1939. Kilgore, A. R.: Tumor and Tumor-like Lesions of the Breast in Association with Pregnancy and Lactation. Arch. Surge 18:2088, 1929. . Kilgore, A. R.: Precancerous Lesions of Breast. West. J. Surge 40: 581, 1932. Lewis, D., and Geschickter, C. F.: Ovarian Hormones in Relation to Chronic Cystic Mastitis. Am. J. Surge 24:280, 1934. Lewis, D., and Geschickter, C. F.: The Relation of Chronic Cystic Mastitis to Carcinoma of the Breast. Surg., Gynec. & Obst. 66:300, 1938. MacDonald, I.: Mammary Carcinoma. A Review of 2,636 Cases. Surg., Gynec. & Obst. 74:75, 1942. . Menville, J. G.: Chancre of the Male Breast Simulating Paget's Cancer of the Nipple. J.A.M.A. 99: 381, 1932. Menville, J. G.: Qynecomastia. Arch. Surge 26:1054, 1933. Moore, J. T.: Carcinoma and other Tumors of the Male Breast. Am. J. Surge 24: 305, 1934. Muller, J.: Uber den feinern Bau und die Formen der krankhaften Geschwiilste. Berlin, G. Reimer, 1838 Nicolson, W. P. and Gillespie, C.: Tuberculosis of the Breast. South. Surge 10:825, 1941.
O O
P P
R
S S
S
W W
PREMALIGNANT LESIONS OF BREAST
1741
Oliver, R. L. and Major, R. C.: Cyclomastopathy; a Physio-Pathological Conception of Some Benign Breast Tumors, with an Analysis of Four Hundred Cases. Am. J. Cancer 21:1, 1934. Oliver, R. L.: Metaplasia in the Breast. Arch. Surge 41:714, 1940. Owens, F. M. and Adams, W. E.: Giant Intracanalicular Fibro-adenoma of the Breast. Arch. Surge 43:588, 1941. Paget, Sir James: St. Barth. Hosp. Rep. 10:87, 1874. Pasternack, J. G. and Wirth, J.E.: Adeno-acanthoma Sarcomatodes of the Mammary Gland. Am. J. Path. 12:423, 1936. Razemon, P., and Bizard, G.: Aberrant Mammary Tumors. Rev. Chir. 67:226, 1929. S~iler, S.: Sarcoma of the Breast. Am. J. Cancer 31:183,1937. Schimmelbusch, C.: Das Cyst-Adenom der Mamma. Arch. f. kline Chir. 44:117, 1892. Speert, H.: Supernumerary Mammae, with Special Reference to the Rhesus . Monkey. Quar. J. BioI. To be published. Wainwright, J. M.: Carcinoma of the Male Breast. Arch. Surge 14:836, 1927. Warren, S.: The Relation of "Chronic Mastitis" to Carcinoma of the Breast. Surg., Gynec. & Obst. 71:257, 1940.
* AND
t
THE following benign breast entities are considered to have a higher incidence of malignant potentiality associated with them than is noted in the breasts of women in the general population not so affected:
1. 2. 3. 4. 5. 6. 7.
Virginal hypertrophy and excessive mammary development Residual lactation mastitis Aberrant mammary tissue Fibroadenoma in pregnancy and at the menopause Intracystic papilloma Mammary dysplasia (chronic cystic mastitis) Keratoses of the nipple; retraction of the nipple; the bleeding nipple
A survey of diagnostic findings and treatment of this group will be given, pointing out the incidence of carcinoma or sarcoma involved, and emphasizing the prognosis before and after malignant changes have occurred. VIRGINAL HYPERTROPHY AND EXCESSIVE MAMMARY DEVELOPMENT
Excessive and persistent enlargement in one or both breasts in the female may occur during adolescence (Fig. 490 and 491) or pregnancy. The cause of the hypertrophy is unknown. Either one or both breasts may be affected. Both epithelium and connective tissue take part in the enlargement (Fig. 492). Growth is progressive for a period of months but rarely extends beyond one or two years' duration. During the period of enlargement, cancer has never been observed but previously hypertrophied breasts have a higher incidence of mammary carcinoma than those of normal size. In our series of twenty-four cases of virginal hypertrophy, two patients subsequently developed mammary carcinoma seventeen to twenty years after the onset of the enlargement. In a study of 1400 cases of infiltrating mammary carcinomas which had complete clinical histories recorded, sixteen patients gave a history of virginal From the Departments of Oncology and Pathology, Georgetown University Medical Center, Washington, D. C. * Professor of Oncology and Director of the Department of Oncology, Georgetown University Medical Center; Attending Surgeon in Oncology, Georgetown University Hospital and Gallinger Municipal Hospital (Georgetown Division). t Professor of Pathology and Director of Department of Pathology, Georgetown University Medical Center; Pathologist-in-Chief, Gallinger Municipal Hospital.
1717
1718
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
hy 1
pr pu fo pi ha ne
M
Fig. 490. Bilateral virginal hypertrophy in a girl 17 years of age.
ti
Fig. 491. Gross specimen of breast removed for benign virginal hypertrophy. Notice the bulky dense structure of the tumor without evidence of loose areolar tissue or fat and the absence of cystic changes.
g th o p p p th fo c T b
PREMALIGNANT LESIONS OF BREAST
1719
hypertrophy. The incidence of cancer, therefore, seems to vary between 1 and 2 per cent. The treatment of virginal hypertrophy is limited to surgery. Plastic procedures are to be carried out in the least bulky breasts. Simple amputation is the treatment of choice in the large congested and painful forms of virginal hypertrophy. In those breasts where the slightest suspicion of cancer exists, exploration is indicated. If malignant change has supervened (usually after many years), radical mastectomy is the necessary treatment. In the male, gynecomastia also increases the susceptibility to carcinoma. Menville found two reports in the literature of malignant change in
Fig. 492. Microphotograph showing hypertrophy of periductal and intralobular tissue in virginal hypertrophy. Lobule formation is minimal.
gynecomastia. Gilbert, in a study of forty-seven patients with cancer of the male breast, found that nine cases were associated with pre-existing or existing gynecomastia. Gynecomastia presents a variety of clinical pictures, the recognition of which is important from the standpoint of prognosis and treatment. The diffuse hypertrophic form seen in early puberty (Fig. 493) often subsides spontaneously or yields to testosterone therapy in the form of testosterone propionate 25 mg., given twice weekly for twelve weeks. In the more chronic fibroadenomatous type it must be carefully distinguished from carcinoma of the male breast (Fig. 494). The rarest form of gynecomastia is that of true feminization of the breast.
1720
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
Surgical excision is indicated for any breast with gynecomastia if any doubt exists as to the diagnosis and, should frozen sections reveal cancer, a radical mastectomy should be performed. RESIDUAL LACTATION MASTITIS
The duration of. symptoms in chronic lactation mastitis ranges from two months to twenty-eight years. The differential diagnosis between
Fig. 493. A photograph of gynecomastia occurring in a Negro boy of 18 years. Cross section of the enlargement is shown below. This form often recedes spontaneously. (After Geschickter, C. F.: Diseases of the Breasts, J. B. Lippincott Co. , Philadelphia, 1945.)
cancer and residual lactation mastitis may be extremely difficult. In eleven of thirty-six patients without frank pus, the inflammatory nature of the lesion was indicated by heat and redness in the overlying skin and by the systemic response of the patients. In the remaining twentyfive cases the area of mastitis was described as a definite mass or nodule. In nineteen of these patients an erroneous diagnosis of malignancy was made, either on the basis of the clinical findings or upon microscopic examination. The long time elapsing after the last lactation, together with the absence of reddening or suppuration, made the diagnosis diffi-
c s c c t o a
g o f
b 2 s
w w o o s
PREMALIGNANT LESIONS OF BREAST
1721
cult in this group of cases. At exploration, the microscopic examination shows residual lactation in some of intact lobules, areas of inflammatory changes and periductal accumulations of wandering cells. The lining cells of ducts are increased in number and are undergoing desquamation. In areas, little remains but a few acini or tubular structures, some of which are partly destroyed, embedded in fibrous tissue (Figs. 495 and 496). McDonald found that in women with cancer of the breast who had
Fig. 494. Microscopic section of a more chronic type of fibroadenomatous gynecomastia. Note the proliferation of the duct epithelium. Such lesions when of long standing may show malignant changes and must be carefully distinguished from carcinoma.
borne children, 42 per cent had had abnormal lactation compared with 20 per cent in the control group. Wainwright had previously found a similar incidence.. in his study. Among 1260 cases of infiltrating mammary cancer occurring in parous women, seventy-eight (or 6 per cent) gave a history of lactation mastitis with or without abscess formation: In only thirty-eight (or 3 per cent) of these patients, however, was the cancer related definitely to the scar or the residual lump. From these thirty-eight cases the following observations on cancer in lactation mastitis are made. The interval be-
1722
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
tween mastitis and the appearance of mammary cancer averaged twentyone years. Age distribution extended from 39 to 67 years. The onset of the malignant growth was related to rapid enlargement of a pre-existing lump, to the development of a mass beneath a scar, to the appearance
m p y
c o u e r f
4 Fig. 495. Upper, Gross specimen with nipple attached showing extent of changes associated with residual lactation mastitis. Lower, Cross section of gross specimen showing the large firm indurated mass, leaving doubt as to the diagnosis unless microscopic sections are studied.
of tenderness in the quiescent lesion, or to changes in the overlying skin. The symptoms referable to the supervening malignant change were usually of short" duration as the growth progressed rapidly. Among our cases the prognosis was worse than in those cases of cancer arising during pregnancy or during active lactation. All patients were treated by radical
w i m m a g T s
PREMALIGNANT LESIONS OF BREAST
1723
mastectomy except one on whom a palliative simple mastectomy was performed. No patient was cured, though one individual lived eight years after radical mastectomy and then died of metastases.
Fig. 496. Microscopic section of residual lactation mastitis. Inflammatory changes are present. The duct and lobule regions show periductal accumulation of wandering cells. Lining cells in some areas may be increased in number and undergo desquamation. Cancer has been found developing in such areas in thirtyeight instances from a series of seventy-eight patients who gave a history of residual lactation mastitis of the chronic type with or without previous abscess formation. .
ABERRANT MAMMARY TISSUE
A distinction must be drawn between supernumerary breasts (Fig. 497, A) which have either nipple or areola (or both), in combination
with persistent or atrophic gland tissue, and aberrant breast tissue which is without nipple or areola (Fig. 497 B). In the older literature the statement is frequently found that tumor formation is relatively more common in the supernumerary breast than in the normal organ. Spcert and also de Cholnoky, in reviewing the subject, indicate that the evidence of greater frequency of cancer in the supernumerary breasts is lacking. There is evidence, however, that aberrant axillary mammary tissue (not supernumerary breasts) is more prone to malignant change than normal breast parenchyma (Matti, Razemon and Bizard, Biancheri). The most common tumors found in aberrant breast tissue are fibroadenoma and
1724
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
carcinoma. Carcinoma is more frequent than benign tumor formation in aberrant mammary tissue. It is usually found only in proximity to the normal breast, that is, in the axillary, sternal or clavicular regions. In our series there have been seven axillary aberrant breast cancers and two such lesions were situated along the sternum.
A
B
t s p t s
n o r
Fig. 497. A, Photograph of female patient with a supernumerary nipple and breast at the base of the right axilla. B, Photograph of a male patient with aberrant breast tissue and without a nipple in the right axillary region.
The symptoms included swelling, tenderness and pain or discomfort in using the arm. These findings existed from four to twenty-four months before treatment was instituted. Where cancer existed, the tumors varied from 2 to 8 em. in diameter. In the axilla the tumor was surrounded by fat or indurated tissue. In addition, many involved lymph nodes were seen in the majority of cases. The prognosis is exceedingly poor where cancer is found. Only one patient lived beyond the five-year period, dying ultimately of metastases. The treatment for aberrant mammary tissue consists of exploration for diagnosis, followed by radical mastectomy when cancer is found. Excision is indicated when any tumor formation is present in supernumerary breasts (Fig. 498). All aberrant breast nodules at the periphery of
m b d s t n t b t T p b r
PREMALIGNANT LESIONS OF BREAST
1725
the breast, especially in the axilla or along the sternum, must be held suspect until proved otherwise. Experience, of course, has shown that primary axillary cancer may extend into the mammary gland and, also, that a minute primary breast cancer escaping detection may be responsible for an axillary growth.
Fig. 498. Microscopic section from localized hypertrophy found in a supernumerary breast. Note the duct and lobule lining cell proliferation. Such areas occasionally give rise to carcinomatous change, and are more often seen in aberrant breast tissue not related to supernumerary breast with nipple formation.
FIBROADENOMA IN PREGNANCY AND AT THE MENOPAUSE
The rapid growth of fibroadenoma in pregnancy and the various morphological changes that occur in these tumors during lactation have been described by us in detail elsewhere. Enlargement is more rapid during the first half of pregnancy than during the second. Increase in size late in pregnancy usually results from secretory changes. Most often there is rapid onset in growth of a pre-existing firm, circumscribed breast nodule; multiple growths may be present. The tumor must be differentiated from cancer, cystic disease or some other rare, firm lesion of the breast. The lack of retraction of the nipple or of atrophy of the skin, together with the average age incidence, are helpful points in diagnosis. The tumors are composed of a growth of ducts and an abundance of periductal connective tissue. The rapid growth and the variety of bizarre microscopic changes which the fibroadenoma may undergo in response to hormonal influences of gestation and lactation may lead to
1726
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
d 4 i
c t t d
c
Fig. 499. A photomicrograph of lactating changes in fibroadenoma showing areas of hyalinized fibrous tissue, dilated ducts and lobular acini. The hyalinized stroma is sometimes cellular and resembles sarcoma.
s
Fig. 500. A microphotograph of lactating fibroadenoma with development of early carcinoma. Note the proliferating carcinoma with acinar arrangement of cells.
b m f t J i o b i t m
PREMALIGNANT LESIONS OF BREAST
1727
difficulties in diagnosis and arouse suspicion of malignant change (Figs. 499 and 500). Fortunately, however, we have observed cancer developing in lactating fibroadenoma only twice in forty-four patients. Prompt excision of fibroadenomas is indicated, particularly during the child-bearing period, in order to avoid the difficulties in diagnosis and treatment associated with rapidly enlarging tumors in pregnancy and lactation. There is general agreement that mammary cancer developing during pregnancy or lactation is unfavorably influenced. During pregnancy the malignant change in fibroadenoma is a carcinomatous one (Fig. 500). However, malignant changes occur in these
Fig. 501. Patient with giant mammary myxoma showing a great increase in size of the breast which is nodular, firm and with evidence of ulceration.
benign lesions under other conditions. Toward the menopause, giant myxoma may develop in fibroadenoma, slowly growing over a period of five or six years with rapid enlargement toward the end (Fig. 501). This type of menopausal giant mammary myxoma was first described by Johannes Muller in 1836. The tumors are large, with great cystic spaces into which fibrous polypoid masses project. These masses are made up of myxomatous connective tissue in polypoid fibrous structures covered by cuboidal epithelium as seen under the microscope (Fig. 502). There is a definite incidence of sarcoma in this group. The differentiation between giant myxoma and fibrosarcoma is not easy and requires careful microscopic study and experience in some cases. If sarcomatous change
1728
MURRAY M. COP·ELAND, CHARLES F. GESCHICKTER
is found, amputation of the breast including the pectoral fascia, without axillary dissection, is indicated. The lesions do not as a rule metastasize to regional lymph nodes. Wide local excision is indicated for the benign lesions. Pasternack and Wirth collected thirty-one cases of large fibroadenomas from the literature in which the lining epithelium of ducts or cysts underwent squamous cell metaplasia. Oliver reported three cases among 600 instances of fibroadenoma. The authors have observed such changes in an additional three cases, making a total of thirty-seven lesions. with squamous cell metaplasia. Such a finding is more common in giant mam-
n n
tis mic Fig. 502. High power photomicrograph of giant myxoma showing marked hypertrophy of periductal fibrous tissue with polypoid masses projecting into cystic spaces covered by cuboidal epithelium. This lesion is secondary to pre-existing fibroadenoma.
mary myxoma than in ordinary fibroadenoma. From among the thirtyseven cases with squamous metaplasia, six instances of squamous cell carcinoma have been recorded (Foot and Moore, Haagensen, Pasternack and Wirth, Geschickter). Squamous cell metaplasia is a rare finding in fibroadenoma, but cancer developing in squamous cell metaplasia found in fibroadenoma is not rare. Should squamous carcinoma be found in a fibroadenoma or giant myxoma, radical mastectomy should be performed.
T in san exi and opa pres or A from 503 the
PREMALIGNANT LESIONS OF BREAST
1729
INTRACYSTIC PAPILLOMA
Benign intracystic papilloma includes (1) papillary invaginations of the larger ducts; (2) intracystic papillomas; and (3) papillary hyperplasia which occurs in adenosis of the breast. The condition, with the exception of papillary changes seen in patients with adenosis of the breast, which will be ,considered elsewhere, occurs usually in women near, at, or beyond the menopause. It occurs with equal frequency in nulliparous and in parous women.
Fig. 503. Intracystic papilloma. Drawing shows proliferation of adenomatous tissue at base of the cyst and beginning infiltration of the cyst wall. There was microscopic evidence of malignant change.
The tumors vary from one to several centimeters in size, occur usually in the central zone of the breast and are frequently associated with a sanguineous discharge from the nipple. Evidence of a lump may have existed for from six months to five years. The mass is soft, compressible and usually freely movable; it is shown on transillumination to be an opaque area; and causes bloody discharge from the nipple when compressed. The tumor has at times been referred to as a low grade papillary or duct cancer (Gray and Wood). Although the authors believe that it is possible to distinguish benign from malignant papillomas of the breast on pathological grounds (Figs. 503 and 504), it must be pointed out that in 17 per cent of our cases the lesions were multiple and approximately 5 per cent were bilateral. 7·
1730
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
Where simple excision was the treatment used in forty-eight cases followed by us, eight had further operations with subsequent papillomas and three had radical mastectomies for papillary cystadenocarcinoma. This type of benign tumor is also capable of giving rise to a gelatinous carcinoma. When simple excision for intracystic papilloma is done, recurrence can be expected in around 20 per cent of patients so treated. Six to 8 per cent of the recurrences will be in the form of malignant change. The
Fig. 504. Photomicrograph of malignant papilloma occurring in the wall of a large cyst. Stalks and cyst walls of such lesions must be carefully studied microscopically for evidence of malignant change and infiltration of surrounding breast tissue.
majority of recurrences of intracystic papilloma are due to the fact that this condition may affect the duct system diffusely or bilaterally and at the time of excision the clinician is only aware of the lesion presenting symptoms. MAMMARY DYSPLASIA
More than a hundred years ago Sir Benjamin Brodie recognized the cystic form of mammary dysplasia as a benign condition of the breast
w h . p f o b l d a
m g le fo es
fo di
PREMALIGNANT LESIONS OF BREAST
1731
and .observed that it was more common in unmarried and childless women (average 35 years). All forms of mammary dysplasia follow this rule and it is, therefore, a disease of increasing incidence in women of the American population. Mastodynia. Of the three forms of mammary dysplasia, simple mammary nodosity with pain is the most common and least serious. It is common in women between the ages of 20 and 40 years. Married women predominate in a ratio of 3 to 1. It is characterized by discomfort, gradual in onset over a period of months, worse in the premenstruum and referred to a portion of one or both breasts (usually upper and outer third), which is more tender, firmer and thicker than the surrounding breast. The defective lobule formation, as demonstrated in recent studies, is due to reduced function of the corpus luteum. Normal lobule formation is dependent on the proper ratio of estrogen and luteal hormones. The authors have followed 310 cases of mastodynia for more than five years before observing a single case of mammary carcinoma associated with this form of dysplasia. This married patient had mastodynia fifteen years before showing evidence of cancer. She had gone through a normal pregnancy twelve years prior to developing the malignant lesion and had been free of the mastodynia since that time. The cancer developed in aberrant breast, apparently unrelated to the previous mastodynia. The treatment of mastodynia is varied. Once the diagnosis of cancer or true infection has been ruled out, simple supportive measures are worthwhile, including reassurance and a breast support (brassiere). Estrogen has proved effective in controlling the condition. Testosterone pro. pionate in doses of 25 mg. per week for a short while has proved satisfactory in a few cases, but progesterone therapy is the treatment of ·choice. Patients have shown improvement when progesterone has been administered in 5 mg. doses hypodermically twice a week for the last two weeks of one or two consecutive cycles with an effective total dose ranging between 20 to 40 mg., two or more years having elapsed after endocrine therapy without recurrence of symptoms. . Cystic Disease. Cystic disease is the next most common form of mammary dysplasia. Women at or near the menopause formthe largest group of patients, usually between the ages of 41 and 45 years. Childless women predominate in the ratio of 3 to 2. One of us (C. F. G.) has found evidence to support the probability that an intense or unopposed estrogenic stimulus results in the formation of the cysts. The symptoms of cystic disease usually appear either abruptly or exist for a relatively short time (days or weeks). The chief complaint is the discovery of a lump. Mild pain, soreness and a burning or sticking sen-
1732
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
e w
p t i t B A .\ specimen of a large cyst (blue-domed) B Fig. 505. A, Photograph of gross occurring in a patient aged 45 years. B, Photograph of cross section of the wall (blucyst ·d m d ) occurshowing smooth lining without evidence of papillomatous formation. lion of Lhc .y -L wall u ' formati n.
d m l p 5
p w o o p c
Fig. 506. Microphotograph of cysts of the breast with typical cuboidal cell lining. The neighboring ducts are dilated. The cysts are filled with coagulated secretion.
o p i t f u p e e "
PREMALIGNANT LESIONS OF BREAST
1733
sation, prior to the appearance of the cystic lump, are occasionally observed. The breasts are usually fairly large or adipose and the cysts are found proximal to the breast periphery. The tumor is round, smooth, tense and freely movable and frequently fluctuates. Cysts may change in size and tend to. disappear in about 7 per cent of the cases. In a large number of patients only one cyst of appreciable size is found, but single cysts may be found in both breasts (11 per cent). Multiple cysts are found in one or both breasts in 25 per cent of cases at the first examination. They occur in a slightly younger age group and the symptoms are similar to those associated with adenosis. The cysts usually can be transilluminated. The majority of them are easily aspirated, yielding a cloudy or a serous fluid. A thick, fibrous, walled cyst deep in the breast makes diagnosis difficult and, if aspiration is unsuccessful, exploration should be resorted to. The treatment of choice is excision of single cysts (84 per cent of the patients are free from further complaints). In 15 per cent of the patients other cysts develop in the breast. Aspiration may be employed if the breasts are carefully watched subsequently. Recurrent tumors of the breast in patients past the menopause must be accurately diagnosed. The mammary cyst appears as a tense, bluish, walled cyst embedded in dense, fibrous stroma (Fig. 505). Multiple small cysts and dilated ducts may be seen in the surrounding tissue. Lobule structure is poor. The lining epithelium of the cyst is often replaced by fibrous tissue, or the persistent cuboidal epithelium contains eosin-staining cytoplasm (Fig. 506). Cancer cysts and intracystic papillomas are not the result of this process. The authors have followed for more than five years 445 patients with cystic disease treated by simple excision or exploration and have observed five cases of associated mammary cancer. This agrees with other observations in the literature (Warren) that it is twice the expected rate. It is still low enough, however, to make conservative procedures the treatment of choice. Adenosis of the Breast. This is, fortunately, the least common form of mammary dysplasia, since it is the most serious in many of its aspects. Adenosis (Schimmelbusch's disease) is most frequently observed in women between the ages of 35 and 44 years. It is characterized by the occurrence, in one or both breasts, of multiple nodules which measure from Imm. to 1 cm. in diameter and are fusually distributed about the upper and outer hemisphere (Fig. 507). In one-third of the patients pain is a conspicuous feature. The breasts, as in mastodynia, are thickened, granular and tender with the addition of multiple nodules. An edge can be palpated at the periphery of the diseased portion. This "caking" or induration may at times suggest cancer.
1734
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
The pathologic process may be limited or diffuse in one breast or in both. Throughout the breast parenchyma, increased periductal and perilobular fibrous tissue, small cysts, minute adenomas, papillomas and dilated ducts are characteristic (Fig. 508). In advanced cases, intraductal hyperplasia and the epithelial proliferation of acini closely resemble changes seen in various forms of cancer. The patients fall into two endocrine groups: (1) patients in early sexual maturity with small breasts due to stunting from high estrogenic
a
Fig. 507. Drawing of cross section of a breast with typical changes in adenosis (Schimmelbusch's disease). Note the cystic areas and small nodulations made up of adenomatous and papillary tissue. In the base of the breast beneath the nipple there is noted a solid area revealing malignant change developing within an adenomatous area.
stimulation in adolescence (C. F. G.); (2) patients of 30 years of age or more, who have characteristic changes in the breast of one or more year's duration, due to prolonged moderate hyperestrinism (C. F. G.) with pain and menstrual complaints and, usually, psychically upset. These symptoms are common in both groups. While the changes seen in mammary dysplasia are not essential to the development of mammary cancer, they do represent changes due to hyperestrinism which, experimentally, leads to the development of breast cancer in animals. Clinically, we have found that among 150 pa-
of
tie cid
PREMALIGNANT LESIONS OF BREAST
1735
Fig. 508. Photomicrograph of adenosis of breast showing intracystic papillomas and nonencapsulated epithelial proliferation of the lobules.
Fig. 509. Photomicrograph of cystic adenocarcinoma developing in adenosis of the breast.
tients with adenosis of the breast who were carefully followed, the incidence of cancer was 4 per cent (5 cases), while among those with cystic
1736
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
disease, the incidence was 0.79 per cent. The incidence of breast cancer among women as a whole is 0.42 per cent. Therapy in adenosis consists of surgical investigation of all doubtful nodules (Fig. 507). Biopsies which show cancer (Fig, 509) indicate a radical mastectomy. Estrogenic therapy is not satisfactory in adenosis and is unsafe to use. Aspiration of cysts may be indicated to obliterate them. Progesterone for symptomatic relief, administered in 10 mg. doses hypodermically twice a week, giving from 40 to 120 mg. as a total dose between two or three menstrual cycles, is the treatment of choice. Recurrence of discomfort may be persistent or again encountered after two or more years. RETRACTION OF THE NIPPLE; KERATOStS OF THE NIPPLE; THE BLEEDING NIPPLE
Congenital retraction of the nipple, nonpuerperal serous discharge from the nipple and postlactation milky discharge from the nipple (galactorrhea) do not predispose to cancer of the breast or nipple, in our experience. On the other hand, keratotic lesions of the nipple or areola may represent the early stages of cancer or constitute a precancerous lesion. Intermittent retraction of the nipple or acquired retraction of the nipple may be a symptom of carcinoma already present, although the retraction cannot be classified as having any bearing on the etiology of the disease. Paget's cancer of the nipple, which ultimately results in ulceration of this organ and the formation of a palpable tumor in the breast beneath, is one of the more malignant forms of mammary carcinoma. A number of lesions of the nipple must be differentiated from this disease and some of these must be looked upon as early stages or premalignant phases of this form of carcinoma. As a rule, Paget's cancer is preceded by either a red, granular nipple, by a shallow ulceration or fissure, or by a scaly keratotic lesion which ultimately weeps and ulcerates. The earliest stages of the tumor may arise in the ampulla and, in this location, the premalignant phases cannot be clinically observed. The persistent keratotic, cr~cked or irritated nipple must, therefore, be biopsiedin order to determine the earliest phase of the disease. In Paget's carcinoma of the nipple, the underlying ductal system is involved in nearly every case and a radical mastectomy is essential for cure (Figs. 510, 511 and 512). In cases in which the nipple is widely excised, with postoperative breast irradiation, recurrence and axillary metastases are the rule. Fifty cases of Paget's cancer, with or without palpable tumor in the breast parenchyma, have been traced and, of this number, twenty-four (48 per cent) survived the five-year period. Keratoses, fissures, ulcerations and red, granular changes in the nipple
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PREMALIGNANT LESIONS OF BREAST
1737
Fig. 510. Gross specimen of Paget's disease of the breast with typical Paget's cancer of the skin and associated transitional carcinoma of the underlying ducts. hr('[ t \\ i h t 'pit'aI Pug it iOIl tI (·Uf(·iIlOIllU of t h(' \llld .r1 ·illg dll(:
Fig. 511. Microphotograph of Paget's carcinoma involving the skin of the ni pple and areola.. Note the typical pagetoid cells in the tumor.
should be treated by excision of the nipple, with a margin of skin and a core of underlying ducts and fatty tissue, if the lesion fails to heal
1738
MURRAY M. COPELAND, CHARLES F. GESCHICKTER
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Fig. 512. Microphotograph of ducts beneath the nipple showing proliferation of tumor cells (transitional cell carcinoma), some of which are forming new ducts.
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B B . Fig. 513. Patient with bilateral keratotic changes of the nipples. The nipples are encrusted and there is edema of the surrounding areola. · Th nipp\
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B
PREMALIGNANT LESIONS OF BREAST
1739
within three to four weeks after cleansing and protective measures. If cancer is found, radical mastectomy is indicated. If cancer is not found; local excision will suffice. The most definite precancerous lesion of the nipple is the scaly keratotic area that fails to heal when washed daily with soap and water followed by alcohol and protected with simple bland ointment, such as petrolatum (Fig. 513). Such a keratotic area can be differentiated from true eczema which usually involves the areola as well as the nipple and other portions of the body, including the ears and the flexor surfaces of the extremities. The incidence of benign and malignant keratotic lesions of the nipple can be judged from the following experience of the authors. During the same period in which seventy-two cases of Paget's cancer were observed, fifty-two patients with benign keratosis, some of which were complicated .by ulceration, were treated. Intracystic papilloma of the ampulla of the nipple, with malignant change, also occurs and, occasionally, is bilateral. The prognosis is better than in Paget's cancer. More rarely, sweat gland cancer, or ordinary basal or squamous cell cancer, is observed in the areola and has a better prognosis than Paget's cancer. A serological test for syphilis should always be performed before surgery. Chancre of the nipple may simulate the disease under discussion. Sanguineous discharge from the nipple may be a symptom of cancer already present or, more frequently, 'accompanies a benign intracystic papilloma which is a premalignant lesion. Fourteen per cent of all mammary carcinomas will be accompanied by a sanguineous discharge from the nipple at the time of clinical examination. However, in only 4 per cent of all breasts examined is a sanguineous discharge the earliest sign of cancer. Fifty per cent of all intracystic papillomas will give a history of sanguineous discharge (a precancerous lesion). In Schimmelbusch's disease (adenosis) sanguineous discharge from the breast is noted in 4 per cent of the cases (a precancerous lesion). The practical point of the matter is that a sanguineous discharge from the breast nipple is an indication of a malignant or premalignant lesion until proved otherwise by surgical exploration. REFERENCES Biancheri, T.: Carcinoma in aNode of Aberrant Accessory Mammary Tissue. Pathologica 24:401,1932. Bloodgood, J. C.: Paget's Disease of the Female Nipple. Arch. Surg. 8:461, 1924. Bloodgood, J. C.: The Treatment of Tumors of the Breast During Pregnancy . and Lactation. Arch. Surg. 18:2079, 1929. Bloodgood, J. C.: Borderline Breast Tumors. Am. J. Cancer 16:103, 1932. Brodie, B.: Sero-cystic Tumors of the Breast. Clin. Lectures on Surgery, Lecture 24:206, 1846. Bronstein, I. P.: Gynecomastia. Endocrinology 24:274, 1939.
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-MURRAY M. COPELAND, CHARLES F. GESCHICKTER
Cheatle, G. L. and Cutler, M.: Tumors of the Breast. London, Edward Arnold & Co., 1931, p. 142. de Cholnoky, T.: Supernumerary Breast. Arch.Surg. 39:926, 1939. Cohn, L. C.: Paget's Disease of the Female Breast. Arch. Surge 34:201;1937. Copeland, M. M.: Newer Aspects of Benign Tumors of the Breast. Arch. Surge 55:590, 1947. Copeland, M. M.: Benign Tumors of the Breast and Associated Conditions. S. Dakota J. Med. & Pharm. 2:116, 1948. Cutler, M.: Benign Lesions of the Female Breast Simulating Cancer. J.A.M.A. 101:1217, 1933. Delannoy, E. and Driessens, J.: Sudoriparous Type of Epithelioma of the Breast. Echo Med. du Nord 4:169, 1935. Fisher, G. A., SchoufHer, G. C., Gurney, G. E. and Benshadler, G. H.: Massive Breast Hypertrophy. West. J. Surge 51:349,1943. Foot, N. C. and Moore, S. W.: A Fatal Case of Deep-seated Epidermoid Carcinoma of the Breast with Widespread Metastases. Am. J. Cancer 34:226, 1938. Fox, S. L.: Sarcoma of the Breast. Ann. Surge 100:401, 1934. Gesehickter , C. F., Lewis, D. and Hartman, C. G.: Tumors of the Breast Related to the Oestrin Hormone. Am. J. Cancer 21:828, 1934. Geschickter, C. F. and Lewis, D. D.: Pregnancy and Lactation Changes in Fibroadenoma of the Breast. Brit. M. J. 1:4026, 1938. Geschickter, C. F.: Corpus Luteum Studies. III. Progesterone Therapy in Chronic Cystic Mastitis. Clin. Endocrinol. 1:147, 1941. Geschickter, C. F.: Diseases of the Breast. Philadelphia, J. B. Lippincott Co., 1945. Gilbert, J. B.: Carcinoma of the Male Breast with Special Reference to Etiology. Surg., Gynec. & Obst. 57:451, 1933. Gilbert, J. B.: Pathologic Physiology of Malignant Tumors of the Testis Associated with Breast Hyperplasia. Arch. Surge To be published. Gray, H. K. and Wood, G. A.: Significance of Mammary Discharge in Cases of Papilloma of the Breast. Arch. Surge 42:203, 1941. Haagensen, C. D.: The Bases for the Histologic Grading of Carcinoma of the Breast. Am. J. Cancer 19:285,1933. Harrington, S. W.: Carcinoma of the Breast: Results of Surgical Treatment When the Carcinoma Occurred in the Course of Pregnancy or Lactation and When Pregnancy Occurred Subsequent to Operation (1910-1933). Ann. Surge 106:690, 1937. Hoffman, W. J.: Hormone Therapy of Male Breast Hypertrophy. Am. J. Cancer 36:247,1939. Kilgore, A. R.: Tumor and Tumor-like Lesions of the Breast in Association with Pregnancy and Lactation. Arch. Surge 18:2088, 1929. . Kilgore, A. R.: Precancerous Lesions of Breast. West. J. Surge 40: 581, 1932. Lewis, D., and Geschickter, C. F.: Ovarian Hormones in Relation to Chronic Cystic Mastitis. Am. J. Surge 24:280, 1934. Lewis, D., and Geschickter, C. F.: The Relation of Chronic Cystic Mastitis to Carcinoma of the Breast. Surg., Gynec. & Obst. 66:300, 1938. MacDonald, I.: Mammary Carcinoma. A Review of 2,636 Cases. Surg., Gynec. & Obst. 74:75, 1942. . Menville, J. G.: Chancre of the Male Breast Simulating Paget's Cancer of the Nipple. J.A.M.A. 99: 381, 1932. Menville, J. G.: Qynecomastia. Arch. Surge 26:1054, 1933. Moore, J. T.: Carcinoma and other Tumors of the Male Breast. Am. J. Surge 24: 305, 1934. Muller, J.: Uber den feinern Bau und die Formen der krankhaften Geschwiilste. Berlin, G. Reimer, 1838 Nicolson, W. P. and Gillespie, C.: Tuberculosis of the Breast. South. Surge 10:825, 1941.
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Oliver, R. L. and Major, R. C.: Cyclomastopathy; a Physio-Pathological Conception of Some Benign Breast Tumors, with an Analysis of Four Hundred Cases. Am. J. Cancer 21:1, 1934. Oliver, R. L.: Metaplasia in the Breast. Arch. Surge 41:714, 1940. Owens, F. M. and Adams, W. E.: Giant Intracanalicular Fibro-adenoma of the Breast. Arch. Surge 43:588, 1941. Paget, Sir James: St. Barth. Hosp. Rep. 10:87, 1874. Pasternack, J. G. and Wirth, J.E.: Adeno-acanthoma Sarcomatodes of the Mammary Gland. Am. J. Path. 12:423, 1936. Razemon, P., and Bizard, G.: Aberrant Mammary Tumors. Rev. Chir. 67:226, 1929. S~iler, S.: Sarcoma of the Breast. Am. J. Cancer 31:183,1937. Schimmelbusch, C.: Das Cyst-Adenom der Mamma. Arch. f. kline Chir. 44:117, 1892. Speert, H.: Supernumerary Mammae, with Special Reference to the Rhesus . Monkey. Quar. J. BioI. To be published. Wainwright, J. M.: Carcinoma of the Male Breast. Arch. Surge 14:836, 1927. Warren, S.: The Relation of "Chronic Mastitis" to Carcinoma of the Breast. Surg., Gynec. & Obst. 71:257, 1940.