Inf. 1 Rodiolbn

Oncology Biol.

Phys 1977.

Vol. 2. pp. 739-742.

Pergamon Press.

Printed m the U.S.A

??Current Concepts in Cancer Updated Breast Cancer-

I. Epidemiology,

Introduction

Etiology, Screening

and Detection

and

PHILIPRUBIN, M.D.

BERNARDFISHER,M.D.

Division of Radiation Oncology, University of Rochester Cancer Center, 601 Elmwood Avenue, Rochester, NY 14642, U.S.A.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261, U.S.A. The Role of Thermography mography

Mammographic

Detection of Early Breast Cancer

as Compared

with Mam-

STRAX, M.D. Guttman Institute, 200 Madison Avenue, New York, NY 10016, U.S.A.

PHILIP

ROBERTL. EAGAN,

M.D. Mammography Section, Emory University, Atlanta, GA 30322, U.S.A.

Some Epidemiological Female Breast

Observations

in Cancer

of the

Shadyside Hospital Institute of Radiology, 5230 Center Avenue, Pittsburgh, PA 15232, U.S.A.

SIDNEY J. CUTLER, M.D. Department of Epidemiology, Meyer L. Prentis Cancer Center, Michigan Cancer Foundation, 110 East Warren Avenue, Detroit, MI 48201, U.S.A.

The archetypal and prototypical cancer for women is breast cancer. It is an ever-present threat. To a woman, breast cancer may mean the loss of a structure associated with her feminity, and to her and her family it may mean the disruption of family life and death. There are few of us who have not had a personal encounter with this cancer through a wife, mother, sister, relative or friend, in terms of the problems of detection, diagnosis, and treatment. It comes as no surprise that it is the most common female tumor, accounting for 25% of newly-diagnosed malignancies in women. Unlike most cancers, breast cancer can occur early in life; it is of major concern to the active woman between 30 and 70 years of age. The statistical analysis of its incidence is startling even to those familiar with this tumor. Epidemiological and clinical studies of breast cancer have offered many well-recognized facts as to its presentation, but have offered no insight as to its cause. Among the substantiated facts are that the location of this cancer is more often on the left side than on the right, in the outer quadrant than in the inner, and that this cancer most often occurs in

women who have not borne nor suckled infants. There is a greater risk of developing a second primary lesion in the opposite breast, as 7-10% of all breast cancers occur consecutively and 2% occur concurrently. There is a four-fold increase in incidence in families with a history of breast cancer, suggesting that certain characteristics allowing for breast cancer are hereditary. The classic epidemiological analysis of Wynder et a1.19failed to yield a clear-cut hypothesis explaining the development of cancer or its prevention, which was attributed to hidden endogenous factors that play a key role in breast cancer. Their basic concept was that any factor which can reduce endocrine function (castration, long-term nursing, dietary abnormalities or any other influence) tends to reduce the risk of development of breast cancer. This study showed that a number of factors, including trauma, breast size, nursing and hormonal therapy, previously considered to play some role in the development of breast cancer have not been statistically substantiated. However, the factor of hormonal therapy was considered before the widespread use of birth control pills; the long-term significance of these

Relationship of Pathologic and Some Clinical criminants to the Spread of Breast Cancer

Dis-

EDWIN R. FISHER,M.D.

739

740

Radiation

Oncology

0

Biology

0

Physic\

drugs has yet to be evaluated. Cutler presents epidemiological observations based on his rich experience as an editor of the End Results in Cancer Reports, published by the Department of Health, Education and Welfare.‘.’ In the pursuit of etiological factors, a variety of mice models of both spontaneous and transplantable breast cancers have been carefully analyzed. A statement of research studies by Andermont3 traces the development of inbred strains of mice to study the genetic factors in high and low incidences of breast cancer. By selective mating, it was first determined that the genetic influence was transmitted by the mother, and later, using foster mothers, it was seen to be transmitted during suckling. This factor was considered to be an extrachromosomal influence which introduced the possibility of a viral etiology in breast cancer, often referred to as the Bittner factor.4 The virus is demonstrable in the blood and other tissues in mice, but its presence in the infected animals is as a hyperplastic breast nodule at the onset, which eventually becomes neoplastic. Another important factor is hormonal stimulation. Breeding hastens the appearance of cancer in all susceptible strains. The viral influence is postulated to be latent in hosts for many years, developing into cancer only under certain conditions. The most intriguing data promoting a viral etiology came from Pitelka et al.ls who showed that male mice transmit a nodule-producing virus which causes breast tumors later in the life of the mice. Electron microscopes have shown that tumor viruses have characteristic morphological structure. Type B viruses have been indentified in human mammary carcinomas and milk. Curiously, the particles were found most frequently in large numbers in women who had a family history of breast carcinoma.14 Recent references on this subject are provided.‘.‘6 Although such morphological evidence is suggestive of a viral etiology, further investigation is required before a specific tumor virus can be associated with a cause for such cancers. The primary problem in breast cancer is its detection. Credit belongs to Eagan for demonstrating the effectiveness of mammography. The attention to meticulous technique and the rigorous interpretation of the characteristic features of breast cancer have led to the detection of occult cancer. Crucial to the procedure is high technical quality to allow for the detection of lesions less than 1.0 cm in size and of fine stippled microcalcification, frequently found in malignant breast tumors. The fact that such small cancers are highly curable and may allow for more measures is most enconservative therapeutic couraging. The slow acceptance of mammography by surgeons is history; its value is now widely appreciated. In fact, the pendulum may have swung in

July-August

1977. Volume

2. No.

7 and No.

X

the direction of indiscriminant use. In this series, Eagan and Strax look at the relative value of mammography versus thermography and arrive at similar conclusions. The detection rate for breast cancer is noted for different procedures; in particular. physical examination is compared to radiographic studies with little doubt as to the superiority of the latter. Especially important are the statements on screening and the wider applicability of such demonstration projects in the community at large. The International Classification of Breast Cancer’ advocates a clinical staging based on the T (primary), iV (nodes) and M (metastases) system (Table 1). At first glance it is accurate, but it is detailed, cumbersome, and difficult to remember. However, once read, the broad principles based on Haagensen’s criteria of operability and inoperability” are fully appreciated. Haagensen developed a Columbia Clinical Staging System, lettered A, B, C and D9 which is essentially similar to the International Classification’s Stages I, II, III and IV. Characteristically, Stage I (or Table

1.

Abridged

TNM* system of clssification cinoma of the Breast s

Symbol

Description

TZ

Less than 2cm No skin fixation 2-5 cm Skin tethered or dimpled No pectoral fixation

T3

5-10 cm

TI

Skin infiltrated or ulcerated Pectoral fixation More than 10cm Skin involvement not beyond breast Chest wall fixation No nodes Axillary nodes movable Not significant Significant Axillary nodes fixed Supraclavicular nodes

T4

No NI

N2

N3 MO M

Edema of arm No metastases Metastases including skin involvement beyond breast Four clinical stages designated by TNM symbols

Stage I Stage II Stage III

Stage

*T

of car-

IV

T, Tz T, Tz

No No NI N,

Mo Mo MO Ma TI Nz or NJ MO

Tz Nz or Ns M. T3 No, N,, Nz, or N, M. T4 No, N,, N2, or N3 MO Any combination of T and cluding M

N

symbols

in-

= tumor; N = nodes; M = metastases New American Joint Committee for Cancer Staging modification of this classification proposed this year (1977) will be published later in the series.

Current

concepts

in cancer:

A) is an early breast cancer localized to the breast without axillary nodes; Stage II (or B) is a similar early cancer with palpable axillary nodes; Stage III (or C) is characterized by a locally advanced cancer showing skin infiltration, ulceration, fixation, or edema; and Stage IV (or D) has evidence of distant metastases. The most vexing aspect of end results reporting remains agreement in breast cancer classification. The variations between the Union Internationale Contre le Cancer (UICC) and the America1 Joint Committee for Cancer Staging (AJCCS) were resolved in 1972, but because new information has become available, the staging systems are being changed. The danger is that similar terminologies may be developed which have different meanings or criteria. One way to avoid this would be to separate clinical diagnostic staging from surgical pathologic staging. It is important to utilize the recommended procedures and not to add information acquired from pathology into the clinical stage (Table 1). The pathology of breast cancer has been wellstudied and the World Health Organization’s 1968 histological classification of breast tumors’* is currently widely utilized by pathologists. Although many authors disregard the pathologic type of breast cancer, since most are undifferentiated adenocarcinemas, it is of value to have some grouping which relates to prognosis. Hultborn and Tornberg’s classification” has been generally used. Its important features are the grading of cancer cells as to differentiation, the degree of peripheral infiltration of lymphocytes and plasma cells, and the frequency of mitosis. The advantage of this pathologic finding is the ease with which it can be applied to properly prepared sections, both frozen and permanent. The following presentation is Hultborn and Tornberg’s classification from Ackerman and de1 Regato:’ Type I : Nonmetustasizing

(not invasive) This type consists of intraductal or comedocarcinema without stromal invasion. The manual expression of necrotic tumor from enlarged or thickened mammary ducts after incising the biopsy is peculiar to type I mammary carcinomas. When this type of neoplasm affects the epithelium of the nipple, the signs of Paget’s disease of the breast may exist. It would also include papillary cancer confined to the ducts. Type ZZ: Rarely metastasizing

1. Pure extracellular cancer. 2. Medullary cancer tration. 3. Well-differentiated I of Tarnberg).

(always invasive) mutinous or colloid

with lymphocytic adenocarcinomas

infil(grade

Introduction

0

741

P. RUBIN

1. The pure mutinous carcinomas of type II are recognized easily. When the biopsy is cut, the tumor is seen to be circumscribed and is homogeneously gelatinous. They are soft and have a gray to reddish-brown color. The mucin is always extracellular. 2. Medullary carcinomas of type II have sharply delimited margins, are uniformly soft, have a light gray color, and may contain small focal necroses. Lymphocytic infiltration is prominent. Medullary may be mistaken grossly for carcinomas fibroadenoma. 3. Well-differentiated grade I adenocarcinomas microscopically have discretely circumscribed borders and are highly and uniformly celluarly differentiated. They would include papillary carcinomas extending outside of the ducts. Type ZZZ: Moderately vasive)

metastasizing

(always

in-

1. Adenocarcinoma (grade II of Tiirnberg). 2. Intraductal carcinoma with stromal invasion. Type III tumors comprise those intraductal carcinomas invading the stroma as well as the ordinary infiltrative adenocarcinomas. Actually, all carcinomas not definitely classified as type I, II or IV constitute type III. Type IV:

Highly metastasizing (always invasive) 1. Undifferentiated carcinoma (grade III of Tiirnberg). Type IV carcinomas include the undifferentiated carcinomas having cells without ductal or tubular arrangement and without cellular inflammatory response about them and all types of tumors indisputably invading blood vessels.

General agreement as to which features are poor prognosticators is still emerging. One source which records clinical data, pathologic analysis, treatment, and outcome in a standardized fashion is the National Adjuvant Surgical Breast Group. Fisher clearly identifies the ominous prognostic discriminants in regional nodal metastases. The basis for identifying the number rather than the proportion of involved nodes has been established and this practice is widely utilized in protocol design for adjuvants. The meaning of host resistance, expressed by such features as lymphoid cellular infiltrates in the tumor and sinus histiocytosis, is presented with a well-documented clinical course of patients. His analysis scores the pathologic characteristics of the tumor rather than the host factors, which are presently difficult to identify. The voluminous writing on breast cancer again illustrates the need for uniformity in reporting statis-

742

Radiation Oncology 0 Biology 0 Physics

tics. The presentation of survival data is meaningless unless the data can be compared to other series. The selection of treatment methods should be based on the statistical evaluation of long-term results rather than on experience or common sense. When reading reports it is important to note whether the author is using absolute or relative survival figures. Absolute results are overall figures in which all patients presenting for treatment are accounted for, as opposed to relative results in which selected smaller groups are analyzed. The danger is in the implication that such relative figures can be extrapolated to interpret the whole experience. Although the newer diagnostic procedures have been widely applied for the early detection of breast cancer, the staging work-up of breast cancer patients has been the subject of much debate. Neither mammography nor thermography is currently considered as a staging procedure by the AJCCS, but their capabilities in determining tumor size, satellite lesions, and fixation to fascia or skin dictate that their importance be recognized. Lymphoangiography of breast carcinoma requires that an injection of contrast media be made into the lymphatic vessels on the dorsum of the hand. A correlative radiographic and pathologic study by Kendall et al.‘* of 57 excised axillary nodes indicated that the inaccuracies and pitfalls of this procedure were too numerous to ac-

July-August 1977, Volume 2, No. 7 and No. 8

curately diagnose lymph node involvement by carcinoma. Error was mainly the result of the simulation of nodal metastatic foci by the fat in the hilum and by inflammatory changes. This procedure has no enthusiastic supporters. A special feature in this issue is Ege’s assessment of internal mammary lymphoscintigraphy, correlated with the histologic findings from excised axillary nodes.6 This study indicates that data comparable to the results of surgical excision and histological examination can be obtained by parasternal lymphoscintigraphy, which demonstrates a 35% abnormal rate in the presence of positive axillary nodes. Although these findings do not correlate directly with those of dissecting nodes, studies by Matsuo13 show a good correlation, indicating that lymphoscintigrams are 50% accurate. Perhaps the major issue in the staging of breast cancer is the value of standard radioisotopic procedures for baseline and early detection of metastases. Bone, liver, and brain scans commonly yield positive findings in localized stages, but such findings are often non-specific and costly. False positives for bone scans are high and false negatives for radiographs are high; however, when these are correlated, accuracy is improved. The benefits of such long-term correlative studies are now being documented in the literature.”

REFERENCES

1. Aaronson, S.A., et al.: The search for RNA tumor viruses in human cancer. Progress in Clinical Cancer. New York, Grune & Stratton, 1975, Vol. VI, pp. 51-63. 2. Ackerman, L.D., de1 Regato, J.A.: Cancer: Diagnosis, Treatment and Prognosis, 3rd Edn. St. Louis, Mosby, 1962, p. 1062. 3. Andermont, H.B.: Breast cancer in mice. Ann. Intern. Med. 63: 323-327, 1965. 4. Bittner, J.J.: Possible relationships of the estrogenic hormones, genetic susceptibility of milk influence in the production of mammary cancer in mice. Cancer Res. 2: 710-721, 1942. 5. Copeland, M.M.: America1 Joint Committee on Cancer Staging and End Results Reporting: Objectives and progress. Cancer 18: 1637-1640, 1965. mammary lymphoscintigraphy in 6. Ege, G.: Internal breast carcinoma: A study of 1072 patients. Int. J. Radiat. Oncol. Biol. Phys. 2: 755-761, 1977. 7. End Results in Cancer, Report No. 4. Washington, D.C.: Dept. of Health, Education, and Welfare Publ. No. (NIH) 73-272, 1973. 8. End Results in Cancer, Report No. 5. Washington, D.C.: Dept. of Health, Education and Welfare. In press. 9. Haagensen, C.D.: Diseases of the Breast. Philadelphia, Saunders, 1956. 10. Haagensen, C.D., Kennedy, C.S., Miller, E., Handley, R.S., Thackray, A.C., Butcher, H.R., Dahl-Iversen, E., Tobiassen, T., Williams, I.G., Curwen, M.P., Kaae, S., Johansen, H.: Treatment of early mammary carcinoma: A cooperative international study. Ann. Surg. 157: 157179, 1963. 11. Hultborn, K.A., Tornberg, B.: Mammary carcinoma:

12.

13.

14.

15.

16.

17.

The biologic character of mammary carcinoma studied in 517 cases by a new form of malignancy grading. Acta Radiol. suppl. 196: 1-143, 1960. Kendall, B.E., Arthur, J.F., Patey, D.H.: Lymphangiography in carcinoma of the breast: A comparison of clinical, radiological, and pathological findings in axillary lymph nodes. Cancer 16: 1233-1242, 1963. Matsuo, S.: Studies on the metastasis of breast cancer to lymph nodes-II. Diagnosis of metastasis to internal mammary nodes using radiocolloid. Acta Med. Okayama. 28: 361-371, 1974. Morgan, H.R.: Relationship of viruses to malignant disease in animals and man. Clinical Oncology for Medical Students and Physicians, 5th Edn. New York, American Cancer Society, to be published. Pitelka, D.R., Bern, H.A., Nandi, S., DeOme, K.B.: On the significance of virus-like particles in mammary tissues of C3Hf mice. J. Natl. Cancer. Ins&. 33: 867-885, 1964. Prevost, J.M.: Oncogenic viruses: Implications for human diseases. Part I and part II. Europ. J. Cancer 12: 327-340, 499-510, 1976. Sklaroff, R.B., Sklaroff, D.M.: Bond metastases from breast cancer at the time of radical mastectomy as detected by bone scan. Eight-year follow-up. Cancer

38: 107-111, 1976. 18. World Health Organization Histological Typing of Breast Turnours. Geneva, World Health Organization,

1968. 19. Wynder, E.L., Bross, I.J., Hirayama, T.: A study of the epidemiology of cancer of the breast. Cancer 13: 559601, 1960.