- Email: [email protected]
On the Concept of Carcinoma in Situ of the Breast
Path. Res. Pract, 166, 407-414 (1980)
Department of Pathology, Central Hospital, Esbjerg (Dr. Andersen) and The University Institute of Pathological Anatomy, Copenhagen (Dr. Schiedr), Denmark
On the Concept of Carcinoma in Situ of the Breast J. A. ANDERSEN and T. SCHIODT Summary The concept of carcinoma In situ of the breast is reviewed. A survey of the history, the present state and perspectives of lobular as well as ductal in situ carcinoma is presented.
Introduction After Broders, in 1932, introduced the concept carcinoma In situ also of the female breast, this term has been the subject of many publications. It comprises intraductal, lobular, and the rare intracystic papilliferous carcinoma of the breast, but in this paper we shall restrict ourselves to the two main types. Especially in early papers it is often not quite evident whether the author, are referring to pure in situ forms, combinations, or even cases with invasive foci. Another difficulty, especially to those not taking a special interest in the field, is the concept "minimal cancer". Some authors take this term to comprise carcinoma in Situ, invasive carcinomas having a diameter of less than 5 mm (Hutter, 1971), and forms of carcinoma having a particularly favourable prognosis, whereas others include in it invasive carcinomas having a diameter of less than 5 mm, or even up to 10 mm. What must be considered essential in this connection is the lack of definite morphological diagnostic criteria of the in situ concept. Thus, it is not possible to fix entirely sharp lower and upper limits. Certain benign conditions, e.g. blunt duct adenosis, may cause misinterpretation, particularly by those not very experienced. Moreover, it is at present not possible to fix an exact limit between lobular and ductal carcinoma in situ, It must be mentioned also that the terminology is not quite consistent, primarily in the case of lobular carcinoma In situ. There is a semantic self-contradiction also in the term "carcinoma in situ" as most recently pointed out by Chandler Smith (1978). Does carcinoma in situ mean "cancer now" which has not yet become invasive or does it mean "not cancer now" but possibly later? Instead of carcinoma in situ Chandler Smith suggested the term "epithelial atypia" in order thereby to avoid predicting cancer. Therefore, in the next few years it must be an important task to try to remedy these vague terms and first and foremost arrive at suited criteria which can be reproduced not only by those having a special interest in the field, but preferably also by others.
Historical After Foote and Stewart's eminent study on lobular carcinoma in situ in 1941 more than 10 years went by before the second publication saw the
408 .
J. A. Andersen and T. Schiodt
light of day (Godwin, 1952), and another 10 years before the third (Barnes, 1959). In the first paper Foote and Stewart gave a thorough description of the histology of lobular carcinoma in situ, stating that it was a multicentric and rare type of cancer for which they advised mastectomy. Not until the late 1960's and early 1970'S did the literature bring follow-up studies on patients treated merely by excision (McDivitt et a1., 1967; Haagensen et a1., 1972 and 1978; Wheeler et a1., 1974; Andersen, 1974 and 1977; Rosen and Liebermann, 1978). To-day the clinical significance of lobular carcinoma in situ may therefore be said to have been established in all essentials. While so far many pathologists and clinicians, not least in Europe (and Haagensen in the U.s.A.), have no doubt been sceptical of the malignant potentiality of lobular carcinoma in situ, this scepticism has not applied to intraductal carcinoma. Considering the frequent demonstration of intraductal carcinoma in a large part of breast carcinomas and the conviction in the early literature that intraductal carcinoma had to be interpreted as cancer, it is perhaps not surprising that for many years no major reflections were devoted to its exact clinical significance. Throughout, and to this very day, some form of mastectomy has been advised. Until about 10 years ago intraductal carcinoma was also considered of common occurrence as compared with lobular carcinoma in situ. It was Farrow's paper in 1968 which started the slow change in the views on the mutual and absolute frequency of carcinomas in situ. To-day it is generally accepted that lobular carcinoma in situ is about three times as common as intraductal carcinoma. In the early 1970'S a few publications gave rise to doubt as to the malignancy of intraductal carcinoma, as it was realized that only very few patients with intraductal carcinoma developed recurrence, metastases, or died of invasive breast carcinoma (Silverberg and Chitale, 1973; Westbrook and Gallager, 1975; Millis and Thynne, 1975). Another interesting feature was that intraductal carcinoma was demonstrated more often in the central quadrant of the breast than were invasive breast carcinomas (Westbrook and Gallager, 1975). To these views, however, it may be objected that the treatment - mastectomy - must be assumed to have removed the nidus completely and that intraductal carcinoma is far less often than lobular carcinoma in situ multicentric and bilatera1. Accordingly, these studies did not leave any certainty concerning the clinical significance of intraductal carcinoma. The first indication of the real clinical significance of intraductal carcinoma was afforded by Betsill et a1. (1978). They reported the follow-up of a small series of women who had only had biopsy, a series extracted in retrospect from a larger total materia1. Their investigation appears to in-
Carcinoma in Situ of the Breast . 409
dicate that the subsequent occurrence of invasive breast carcinoma is around 25%, equal to that in lobular carcinoma in situ. However, it revealed the essential difference that invasive breast carcinoma in intraductal carcinoma seems to occur predominantly on the same side and most often close to the scar left by the biopsy. The history of carcinoma in situ in the female breast is an interesting example that relatively few morphological-clinical studies may give a new turn to previously accepted views.
What do we Pretend to Know To-day About Carcinoma in Situ? Lobular carcinoma in situ is a common histological finding, making up, among otherwise benign breast biopsies, 1.5 to 3.5%, depending mainly upon the diagnostic intensity. It may be found also in about 20% of breasts which also harbour intraductal carcinomas and invasive ductogenic carcinomas (Farrow, 1970; Ashikari et al., 1971). Although this lesion may be demonstrated at all ages after puberty, it occurs most often in premenopausal women, with a peak in the forties, the very age at which most biopsies for fibroadenomatosis are made. The multicentricity is not below 7°% and bilateral occurrence not below 3°-35%. Therefore, the lesion must be interpreted as being a diffuse one of the mammary gland tissue in women, but perhaps with a tendency to a peculiar spatial distribution (Lambird and Shelley, 1969). Lobular carcinoma in situ is generally demonstrated by histological examination. Its extent is rarely so massive that it makes up a palpable tumour (Andersen, 1974). In about half the cases the surrounding breast tissue, or rarely the lobular carcinoma in situ itself, contains microcalculi in a quantity and of a size which afford a possibility of mammographic aid in the identification (Hutter et al., 1969). However, lobular carcinoma in situ is most often demonstrated accidentally, during examination of breast tissue removed chiefly because of fibroadenomatosis. On the other hand, the incidence in the general population is unknown. Demonstration of lobular carcinoma in situ means a 7-12 times greater risk of later developing invasive breast carcinoma as compared with an age-corrected general population. Unfortunately, the invasive breast carcinomas occur with equal frequency in the ipsi- and contra-lateral breast (Wheeler et al., 1974; Andersen, 1974; Rosen and Liebermann, 1978). From the time that a lobular carcinoma in situ is demonstrated and until invasive breast carcinoma occurs many years may elapse, even more than 20, and
410 •
J. A. Andersen
and T. Schiodt
there is no evidence to indicate that a particularly large number of invasive breast carcinomas occur during the first years after the demonstration of lobular carcinoma in situ (Andersen, 1977; Haagensen et al., 1978; Rosen and Liebermann, 1978). Attempts at correlating the histological appearances in lobular carcinoma in situ with the subsequent occurrence of invasive breast carcinoma have generally been negative (Andersen, 1974; Haagensen et al., 1978). Enzyme histochemical (e.g. Murad, 197 I), ultrastructural (e.g. Schafer and Bassler, 1969; Murad, 1971; Ozzello, 1971), hormone, and DNA studies (e.g. Toews et al., 1968; Sachs, 1971; Ludwig et al., 1973) have been few and have not yet decisively contributed to solving the main practical problems of this subject. Prior to Broders' definition of carcinoma in situ the intraductal carcinoma was a well-described disease interpreted as carcinoma. However, the previous materials had comprised actual intraductal carcinomas as well as cases having an invasive component. The histological appearances have been well-known for many years and were admirably illustrated by Stewart in 1950. Only a few materials of purely intraductal carcinomas are on record (Gillis et al., 1960; Kraus and Neubecker, 1962; Ashikari et al., 1971 and 1977; Haagensen, 1972; Millis and Thynne, 1975; Westbrook and Gallager, 1975; Carter and Smith, 1977; Betsill et al., 1978). Intraductal carcinoma is multicentric in about 35% of the cases (Ashikari et al., 1971) and bilateral in about 10% (Farrow, 1970). Intraductal carcinoma is fairly rare, lobular carcinoma in situ being about 3 times as common. As a rule - in particular formerly - the lesion has been demonstrated because of a palpable mass, but now we can add the cases demonstrated by mammography and those found by careful histological examination of tissue removed because of other diseases. The mean age of women with intraductal carcinoma is around 55 years. The prognostic significance of intraductal carcinoma has not yet been definitely established. It seems to be similar to that of lobular carcinoma in situ, only with the difference that the carcinoma which develops subsequently is usually ipsilateral (Rosen and Liebermann, 1978) The uncertainty in the literature is particularly marked as regards the question how long the epithelial changes remain purely intraductal. According to Silverberg and Chitale (1973) this is "a very transitory preinfiltrating phase", whereas Millis and Thynne (1975) reported that the two recurrences in their material were still intraductal, one 6 months and the other 7 years after the primary excision. Whether incipient invasion exists in carcinoma in situ has also not been clarified by electron microscopy. Ozzello, in several papers on the light and
Carcinoma in Situ of the Breast . 411
electron microscopy, into a1. in 1959 and 1971, has demonstrated rupture of the basement membrane in cases where light microscopy has indicated purely intraductal carcinoma. However, the question whether benign epithelial hyperplasias may have similar rupture of the basement membrane has not been finally elucidated. On the other hand, an intact basement membrane is no guarantee that invasive growth is not present, as it has been demonstrated (Murad and Scarpelli, 1967; Goldenberg et a1., 1969) that the tumour cells of scirrhous invasive carcinoma may form basement membranes. Serial sections can often disclose invasive foci, but Gallager and Martin (1969) have reported two cases of intraductal carc inoma with axillary metastases , although in "subserial whole organ sections" the breasts had shown only intraductal carcinoma without the classical criteria of invaSIOn.
Perspectives The decisive factors concerning this subject are the difficulty in differentiating the carcinomas in situ primarily from benign conditions and to a lesser extent from invasive carcinoma and that carcinomas in situ are often small, focal changes demonstrated only histologically. Specially interested surgical pathologists can in most cases distinguish the carc inomas in situ with fairly great accuracy, but the problem is a difficult one. It is important, therefore, to develop histological methods for this differentiation, and such methods must be applicable for tissue fixed in formalin and embedded in paraffin. More refined methods, requiring frozen tissue or the like, may of course be of theoretical interest, but they can hardly acquire great importance in the daily identification. To name examples of some of the means that may be used to improve routine identification there is reason to point out the possibility of differentiating lobular carcinoma in situ from carcinomatous involvement of the lobules by differences in the occurrence of sialomucin (Gad and Azzopardi, 1975). Furthermore, interest should be taken in investigating a possible interaction between the proliferating epithelium and the connective tissue immediately surrounding it, a field to which little attention has been paid so far. The method may be electron micro scopy (Ozzello and Sanpitak, 1970) or the use of simpler histochemical reactions, such as the demonstration of alkaline phosphatase activity in the connective tissue around the epithelial proliferation (Jensen and Schiedt, 1971). As regards intraductal carcinoma, the next years may be expected to witness the publication of new materials of cases having only biopsy and
412 •
J. A. Andersen and T. Schiadt
followed for a long time. This work is cumbersome, as it means extracting the cases in retrospect without selection and as it presupposes the possibility of tracing all cases that have been demonstrated.
References Andersen, J. A.: Lobular carcinoma In situ: A long-term follow-up in 52 cases. Acta path. microbiol. scand. Sect. A 82,519-533 (I974) Andersen, J. A.: Lobular carcinoma in situ: A histological study of 52 cases. Acta path. microbiol. scand. Sect. A 82, 735-741 (I974) Andersen, J. A.: Lobular carcinoma in situ of the breast. Cancer 39, 2597-2602 (I977) Ashikari, R., Hadju, S. 1., and Robbins, G. F.: Intraductal carcinoma of the breast (I96o-1969). Cancer 28, rr82-rr87 (I97I) Ashikari, R., Huvos, A. G., and Snyder, R. E.: Prospective study of non-infiltrating carcinoma of the breast. Cancer 39, 435-439 (I977) Barnes, J. P.: Bilateral lobular carcinoma in situ of the breast: Report of 2 cases. Tex. St. J. Med. 55, 581-5 85 (I959) Betsill, W. L., Rosen, P. P., Liebermann, P. H., and Robbins, G. F.: Intraductal car cinoma. Long-term follow-up after treatment by biopsy alone. J. Amer. med. Ass. 239, 1863-1867 (I97 8) Broders, A. c.: Carcinoma in situ contrasted with benign penetrating epithelium. J. Amer. med. Ass. 99, 167Q-1()74 (1932) Carter, D., and Smith, R. R. L.: Carcinoma in situ of the breast. Cancer 40, I I 89-1 193 (I977) Farrow, J. H.: Clinical considerations and treatment of in situ lobular breast cancer. Arner, J. Roentgenol. I02, 652-656 (I968) farrow, J. H.: Current concepts in the detection and treatment of the earliest of the early breast cancers. Cancer 25, 468-477 (I970) foote, F. W., and Stewart, F. W.: Lobular carcinoma in situ: A rare form of mammary cancer. Amer, J. Path. I7, 491-495 (I94I) Gad, A., and Azzopardi, J. G.: Lobular carcinoma of the breast: A special variant of mucin-secreting carcinoma. J. din. Path. 28, 711-716 (I 975) Gallager, H. S., and Martin, J. E.: Early phases in the development of breast cancer. Cancer 24, IQO-II78 (I969) Gillis, D. A., Dockerty, M. D., and Clagett, O. T.: Preinvasive intraductal carcinoma of the breast. Surg. Gynec . Obstet. IIO, 555-562 (1960) Godwin, J. T.: Chronology of lobular carcinoma of the breast: Report of a case. Cancer 5,259-266 (I952) Goldenberg, V. E., Goldenberg, N. S., and Sommers, S. C.: Comparative ultrastructure of atypical ductal hyperplasia, intraductal carcinoma, and infiltrating ductal carcinoma of the breast. Cancer 24, I I 52-1169 (I969) Hutter, R. V. P., Snyder, R. E., Lucas, J. c., Foote, F. W., and Farrow, J. H.: Clinical and pathologic correlation with mammographic findings in lobular carcinoma in situ Cancer 23, 826-839 (I969) Hutter, R. V. P.: The pathologists role in minimal breast cancer. Cancer 28, 1527-1536 (I97 I) Haagenson, C. D.: Diseases of the breast, znd ed., pp. 155-29I. Saunders, PhiladelphiaLondon-Toronto (I972)
Car cinoma in Situ of the Breast . 413 H aagensen, C. D ., Lane, N ., and Latt es, R.: Neoplastic proliferat ion of th e epithelium of the mammary lobul es: Aden osis, lobul ar neopl asia and sma ll cell carcinoma. Surg . Cl in. N. Amer. 52, 497-524 (197 2 ) H aagensen, C. D ., La ne, N ., Latt es, R., and Bodian, c.: Lobul ar neopla sia (so-called lobula r carc inoma in sit u) of th e breast. Cancer 4 2 , 737-769 (1978) Jensen, H., and Schiedt, T. : Str omal response in breast carc inoma and fibr oadenomatosis, estimate d by the aid of th e Alka line Pho sphata se activity. Acta path. microbiol. scand. Sect. A 79, 32 1- 329 (197 1) K raus, F. T., and Neubecker, R. D. : Th e di fferenti al diagnosis of papill ar y tumors of the brea st. Cancer I5 , 444-4 55 (1962) Lambird , P. A., and Shell ey, W. M. : Th e spati al distribution of lobul ar in situ mamm ar y carcinom a. ]. Amer. med . Ass. 210, 689- 69 3 (1969) Lud wig, A. S., Okagaki, T., Richart, R. M., and Lattes, R.: Nuclear DNA content of lobular carcinoma in situ of the breast. Cancer 3I, 1553- 1560 ( 1973) McD ivitt, R. W., Hutter, R. V. P., Foote, F. W., and Stewart , F. W.: In situ lobular carcinoma : A prospective follow-up study indicating cumulative patient risks. J. Amer. med. Ass. 20I, 82-8 6 (1967) Millis, R. R., and Thynne, G. S. ].: In situ intraduct carci noma of the breast: A long term follo w-up stud y. Brit. J . Surg. 62, 957- 962 (1975 ) Murad , T. M., and Scar pelli, D. G.: Th e ult ra stru ctu re of medullary and scirrhous mammary duct car cinoma. Amer. ]. Path. 5°, 335- 345 ( 1967) Mur ad , T. M.: Ultrastru ctu re of ductular carcinoma of the breast (in situ and infilt ra ti ng lobu lar carcinoma) . Cancer 27, 18- 28 (1971) Oz zello, L. : Th e behavior of basement membranes in intra ducta l carc inoma of the breast. Amer. ]. Path. 35, 887-899 (1959) Ozzello, L., an d San pit ak, P.: Epithelial-stromal jun ction of int rad ucta l carcinoma of the breast. Cancer 26, 1186-1198 (1970) Ozzello, L.: Ultra stru cture of intraepithelial carcinomas of th e breast. Cancer 28, 15081515 (197 1) Rosen, P. P., and Lieberman n, P. H .: Lobular carcinoma in situ: Prel imin ary results of a long term follo w-up stu dy, in : "Early di agnosis of breast ca ncer. Methods and result s", Ed. E. Gr und mann and L. Beck, pp, 119- 128. (Ca ncer Campaign, Vol. 1.) Gustav Fischer, Stuttgart-New York (1978) Sachs, H .: Zyrophoromerri sche Unt ersuchun gen bei Prakanzerosen der Mamma. Beitr . path. Anat. I43, 360-377 (1971) Schafer , A., and Bassler, R.: Vergleichende elekrronenmikroskopi sche Untersuchungen am Drii senepithel und am sog. Iobul aren Carcinom der Mamma. Vir chows Arch. Abr, A path. Anal. 346,269-286 (1969) Silverberg, S. G., and Chitale, A. R.: Assessment of significance of pr oportions of intraductal and infiltrating tumor grow th in ductal carci nom a of the brea st. Cancer ]2, 830- 837 (1973) Smith , c.: Carcinoma in situ . Hum . Path . 9, 373-374 (1978 ) Stewart, F. W.: Tumors of the breast. Atlas of Tumor Pathology Sect. I X , fa sc, 34. Armed Forces Institute of Pathology (1950) Toews, H . A., Kata yam a, K . P., Masukawa, T., and Lewison, E. F.: Chromosomes of benign an d mali gnant lesions of th e breast. Canc er 22, 1296- 13°7 (1968) Westbr ook, K. c., and Gallager, H. S.: Intradu ctal carcinoma of the breast. A compa ra tive study . Amer.]. Surg. I30 , 667- 670 (197 5)
414 .
J. A. And ersen
and T . Schiedt
Wheeler, J. E., Enterline, H. T., Roseman, J . M., Tomasulo, J. P., McIlvaine, C. H., Fitts, W. T. , and Kirshenbaum, ]. : Lobular car cinoma in situ of th e brea st : Long term follow-up. Can cer 34, 554-563 (1974)
Received and accepted Januar y 31, 1979
Key words: Breast cancer - Lobular carcinoma in situ - Ductal carcinoma in situ - In traductal carcinoma - Carcinoma in situ Johan A. Andersen, M.D., Chief Pathologist, In stitute of Pathology, Centralsygehuset, DK-6700 Esbjerg, Denmark
Department of Pathology, Central Hospital, Esbjerg (Dr. Andersen) and The University Institute of Pathological Anatomy, Copenhagen (Dr. Schiedr), Denmark
On the Concept of Carcinoma in Situ of the Breast J. A. ANDERSEN and T. SCHIODT Summary The concept of carcinoma In situ of the breast is reviewed. A survey of the history, the present state and perspectives of lobular as well as ductal in situ carcinoma is presented.
Introduction After Broders, in 1932, introduced the concept carcinoma In situ also of the female breast, this term has been the subject of many publications. It comprises intraductal, lobular, and the rare intracystic papilliferous carcinoma of the breast, but in this paper we shall restrict ourselves to the two main types. Especially in early papers it is often not quite evident whether the author, are referring to pure in situ forms, combinations, or even cases with invasive foci. Another difficulty, especially to those not taking a special interest in the field, is the concept "minimal cancer". Some authors take this term to comprise carcinoma in Situ, invasive carcinomas having a diameter of less than 5 mm (Hutter, 1971), and forms of carcinoma having a particularly favourable prognosis, whereas others include in it invasive carcinomas having a diameter of less than 5 mm, or even up to 10 mm. What must be considered essential in this connection is the lack of definite morphological diagnostic criteria of the in situ concept. Thus, it is not possible to fix entirely sharp lower and upper limits. Certain benign conditions, e.g. blunt duct adenosis, may cause misinterpretation, particularly by those not very experienced. Moreover, it is at present not possible to fix an exact limit between lobular and ductal carcinoma in situ, It must be mentioned also that the terminology is not quite consistent, primarily in the case of lobular carcinoma In situ. There is a semantic self-contradiction also in the term "carcinoma in situ" as most recently pointed out by Chandler Smith (1978). Does carcinoma in situ mean "cancer now" which has not yet become invasive or does it mean "not cancer now" but possibly later? Instead of carcinoma in situ Chandler Smith suggested the term "epithelial atypia" in order thereby to avoid predicting cancer. Therefore, in the next few years it must be an important task to try to remedy these vague terms and first and foremost arrive at suited criteria which can be reproduced not only by those having a special interest in the field, but preferably also by others.
Historical After Foote and Stewart's eminent study on lobular carcinoma in situ in 1941 more than 10 years went by before the second publication saw the
408 .
J. A. Andersen and T. Schiodt
light of day (Godwin, 1952), and another 10 years before the third (Barnes, 1959). In the first paper Foote and Stewart gave a thorough description of the histology of lobular carcinoma in situ, stating that it was a multicentric and rare type of cancer for which they advised mastectomy. Not until the late 1960's and early 1970'S did the literature bring follow-up studies on patients treated merely by excision (McDivitt et a1., 1967; Haagensen et a1., 1972 and 1978; Wheeler et a1., 1974; Andersen, 1974 and 1977; Rosen and Liebermann, 1978). To-day the clinical significance of lobular carcinoma in situ may therefore be said to have been established in all essentials. While so far many pathologists and clinicians, not least in Europe (and Haagensen in the U.s.A.), have no doubt been sceptical of the malignant potentiality of lobular carcinoma in situ, this scepticism has not applied to intraductal carcinoma. Considering the frequent demonstration of intraductal carcinoma in a large part of breast carcinomas and the conviction in the early literature that intraductal carcinoma had to be interpreted as cancer, it is perhaps not surprising that for many years no major reflections were devoted to its exact clinical significance. Throughout, and to this very day, some form of mastectomy has been advised. Until about 10 years ago intraductal carcinoma was also considered of common occurrence as compared with lobular carcinoma in situ. It was Farrow's paper in 1968 which started the slow change in the views on the mutual and absolute frequency of carcinomas in situ. To-day it is generally accepted that lobular carcinoma in situ is about three times as common as intraductal carcinoma. In the early 1970'S a few publications gave rise to doubt as to the malignancy of intraductal carcinoma, as it was realized that only very few patients with intraductal carcinoma developed recurrence, metastases, or died of invasive breast carcinoma (Silverberg and Chitale, 1973; Westbrook and Gallager, 1975; Millis and Thynne, 1975). Another interesting feature was that intraductal carcinoma was demonstrated more often in the central quadrant of the breast than were invasive breast carcinomas (Westbrook and Gallager, 1975). To these views, however, it may be objected that the treatment - mastectomy - must be assumed to have removed the nidus completely and that intraductal carcinoma is far less often than lobular carcinoma in situ multicentric and bilatera1. Accordingly, these studies did not leave any certainty concerning the clinical significance of intraductal carcinoma. The first indication of the real clinical significance of intraductal carcinoma was afforded by Betsill et a1. (1978). They reported the follow-up of a small series of women who had only had biopsy, a series extracted in retrospect from a larger total materia1. Their investigation appears to in-
Carcinoma in Situ of the Breast . 409
dicate that the subsequent occurrence of invasive breast carcinoma is around 25%, equal to that in lobular carcinoma in situ. However, it revealed the essential difference that invasive breast carcinoma in intraductal carcinoma seems to occur predominantly on the same side and most often close to the scar left by the biopsy. The history of carcinoma in situ in the female breast is an interesting example that relatively few morphological-clinical studies may give a new turn to previously accepted views.
What do we Pretend to Know To-day About Carcinoma in Situ? Lobular carcinoma in situ is a common histological finding, making up, among otherwise benign breast biopsies, 1.5 to 3.5%, depending mainly upon the diagnostic intensity. It may be found also in about 20% of breasts which also harbour intraductal carcinomas and invasive ductogenic carcinomas (Farrow, 1970; Ashikari et al., 1971). Although this lesion may be demonstrated at all ages after puberty, it occurs most often in premenopausal women, with a peak in the forties, the very age at which most biopsies for fibroadenomatosis are made. The multicentricity is not below 7°% and bilateral occurrence not below 3°-35%. Therefore, the lesion must be interpreted as being a diffuse one of the mammary gland tissue in women, but perhaps with a tendency to a peculiar spatial distribution (Lambird and Shelley, 1969). Lobular carcinoma in situ is generally demonstrated by histological examination. Its extent is rarely so massive that it makes up a palpable tumour (Andersen, 1974). In about half the cases the surrounding breast tissue, or rarely the lobular carcinoma in situ itself, contains microcalculi in a quantity and of a size which afford a possibility of mammographic aid in the identification (Hutter et al., 1969). However, lobular carcinoma in situ is most often demonstrated accidentally, during examination of breast tissue removed chiefly because of fibroadenomatosis. On the other hand, the incidence in the general population is unknown. Demonstration of lobular carcinoma in situ means a 7-12 times greater risk of later developing invasive breast carcinoma as compared with an age-corrected general population. Unfortunately, the invasive breast carcinomas occur with equal frequency in the ipsi- and contra-lateral breast (Wheeler et al., 1974; Andersen, 1974; Rosen and Liebermann, 1978). From the time that a lobular carcinoma in situ is demonstrated and until invasive breast carcinoma occurs many years may elapse, even more than 20, and
410 •
J. A. Andersen
and T. Schiodt
there is no evidence to indicate that a particularly large number of invasive breast carcinomas occur during the first years after the demonstration of lobular carcinoma in situ (Andersen, 1977; Haagensen et al., 1978; Rosen and Liebermann, 1978). Attempts at correlating the histological appearances in lobular carcinoma in situ with the subsequent occurrence of invasive breast carcinoma have generally been negative (Andersen, 1974; Haagensen et al., 1978). Enzyme histochemical (e.g. Murad, 197 I), ultrastructural (e.g. Schafer and Bassler, 1969; Murad, 1971; Ozzello, 1971), hormone, and DNA studies (e.g. Toews et al., 1968; Sachs, 1971; Ludwig et al., 1973) have been few and have not yet decisively contributed to solving the main practical problems of this subject. Prior to Broders' definition of carcinoma in situ the intraductal carcinoma was a well-described disease interpreted as carcinoma. However, the previous materials had comprised actual intraductal carcinomas as well as cases having an invasive component. The histological appearances have been well-known for many years and were admirably illustrated by Stewart in 1950. Only a few materials of purely intraductal carcinomas are on record (Gillis et al., 1960; Kraus and Neubecker, 1962; Ashikari et al., 1971 and 1977; Haagensen, 1972; Millis and Thynne, 1975; Westbrook and Gallager, 1975; Carter and Smith, 1977; Betsill et al., 1978). Intraductal carcinoma is multicentric in about 35% of the cases (Ashikari et al., 1971) and bilateral in about 10% (Farrow, 1970). Intraductal carcinoma is fairly rare, lobular carcinoma in situ being about 3 times as common. As a rule - in particular formerly - the lesion has been demonstrated because of a palpable mass, but now we can add the cases demonstrated by mammography and those found by careful histological examination of tissue removed because of other diseases. The mean age of women with intraductal carcinoma is around 55 years. The prognostic significance of intraductal carcinoma has not yet been definitely established. It seems to be similar to that of lobular carcinoma in situ, only with the difference that the carcinoma which develops subsequently is usually ipsilateral (Rosen and Liebermann, 1978) The uncertainty in the literature is particularly marked as regards the question how long the epithelial changes remain purely intraductal. According to Silverberg and Chitale (1973) this is "a very transitory preinfiltrating phase", whereas Millis and Thynne (1975) reported that the two recurrences in their material were still intraductal, one 6 months and the other 7 years after the primary excision. Whether incipient invasion exists in carcinoma in situ has also not been clarified by electron microscopy. Ozzello, in several papers on the light and
Carcinoma in Situ of the Breast . 411
electron microscopy, into a1. in 1959 and 1971, has demonstrated rupture of the basement membrane in cases where light microscopy has indicated purely intraductal carcinoma. However, the question whether benign epithelial hyperplasias may have similar rupture of the basement membrane has not been finally elucidated. On the other hand, an intact basement membrane is no guarantee that invasive growth is not present, as it has been demonstrated (Murad and Scarpelli, 1967; Goldenberg et a1., 1969) that the tumour cells of scirrhous invasive carcinoma may form basement membranes. Serial sections can often disclose invasive foci, but Gallager and Martin (1969) have reported two cases of intraductal carc inoma with axillary metastases , although in "subserial whole organ sections" the breasts had shown only intraductal carcinoma without the classical criteria of invaSIOn.
Perspectives The decisive factors concerning this subject are the difficulty in differentiating the carcinomas in situ primarily from benign conditions and to a lesser extent from invasive carcinoma and that carcinomas in situ are often small, focal changes demonstrated only histologically. Specially interested surgical pathologists can in most cases distinguish the carc inomas in situ with fairly great accuracy, but the problem is a difficult one. It is important, therefore, to develop histological methods for this differentiation, and such methods must be applicable for tissue fixed in formalin and embedded in paraffin. More refined methods, requiring frozen tissue or the like, may of course be of theoretical interest, but they can hardly acquire great importance in the daily identification. To name examples of some of the means that may be used to improve routine identification there is reason to point out the possibility of differentiating lobular carcinoma in situ from carcinomatous involvement of the lobules by differences in the occurrence of sialomucin (Gad and Azzopardi, 1975). Furthermore, interest should be taken in investigating a possible interaction between the proliferating epithelium and the connective tissue immediately surrounding it, a field to which little attention has been paid so far. The method may be electron micro scopy (Ozzello and Sanpitak, 1970) or the use of simpler histochemical reactions, such as the demonstration of alkaline phosphatase activity in the connective tissue around the epithelial proliferation (Jensen and Schiedt, 1971). As regards intraductal carcinoma, the next years may be expected to witness the publication of new materials of cases having only biopsy and
412 •
J. A. Andersen and T. Schiadt
followed for a long time. This work is cumbersome, as it means extracting the cases in retrospect without selection and as it presupposes the possibility of tracing all cases that have been demonstrated.
References Andersen, J. A.: Lobular carcinoma In situ: A long-term follow-up in 52 cases. Acta path. microbiol. scand. Sect. A 82,519-533 (I974) Andersen, J. A.: Lobular carcinoma in situ: A histological study of 52 cases. Acta path. microbiol. scand. Sect. A 82, 735-741 (I974) Andersen, J. A.: Lobular carcinoma in situ of the breast. Cancer 39, 2597-2602 (I977) Ashikari, R., Hadju, S. 1., and Robbins, G. F.: Intraductal carcinoma of the breast (I96o-1969). Cancer 28, rr82-rr87 (I97I) Ashikari, R., Huvos, A. G., and Snyder, R. E.: Prospective study of non-infiltrating carcinoma of the breast. Cancer 39, 435-439 (I977) Barnes, J. P.: Bilateral lobular carcinoma in situ of the breast: Report of 2 cases. Tex. St. J. Med. 55, 581-5 85 (I959) Betsill, W. L., Rosen, P. P., Liebermann, P. H., and Robbins, G. F.: Intraductal car cinoma. Long-term follow-up after treatment by biopsy alone. J. Amer. med. Ass. 239, 1863-1867 (I97 8) Broders, A. c.: Carcinoma in situ contrasted with benign penetrating epithelium. J. Amer. med. Ass. 99, 167Q-1()74 (1932) Carter, D., and Smith, R. R. L.: Carcinoma in situ of the breast. Cancer 40, I I 89-1 193 (I977) Farrow, J. H.: Clinical considerations and treatment of in situ lobular breast cancer. Arner, J. Roentgenol. I02, 652-656 (I968) farrow, J. H.: Current concepts in the detection and treatment of the earliest of the early breast cancers. Cancer 25, 468-477 (I970) foote, F. W., and Stewart, F. W.: Lobular carcinoma in situ: A rare form of mammary cancer. Amer, J. Path. I7, 491-495 (I94I) Gad, A., and Azzopardi, J. G.: Lobular carcinoma of the breast: A special variant of mucin-secreting carcinoma. J. din. Path. 28, 711-716 (I 975) Gallager, H. S., and Martin, J. E.: Early phases in the development of breast cancer. Cancer 24, IQO-II78 (I969) Gillis, D. A., Dockerty, M. D., and Clagett, O. T.: Preinvasive intraductal carcinoma of the breast. Surg. Gynec . Obstet. IIO, 555-562 (1960) Godwin, J. T.: Chronology of lobular carcinoma of the breast: Report of a case. Cancer 5,259-266 (I952) Goldenberg, V. E., Goldenberg, N. S., and Sommers, S. C.: Comparative ultrastructure of atypical ductal hyperplasia, intraductal carcinoma, and infiltrating ductal carcinoma of the breast. Cancer 24, I I 52-1169 (I969) Hutter, R. V. P., Snyder, R. E., Lucas, J. c., Foote, F. W., and Farrow, J. H.: Clinical and pathologic correlation with mammographic findings in lobular carcinoma in situ Cancer 23, 826-839 (I969) Hutter, R. V. P.: The pathologists role in minimal breast cancer. Cancer 28, 1527-1536 (I97 I) Haagenson, C. D.: Diseases of the breast, znd ed., pp. 155-29I. Saunders, PhiladelphiaLondon-Toronto (I972)
Car cinoma in Situ of the Breast . 413 H aagensen, C. D ., Lane, N ., and Latt es, R.: Neoplastic proliferat ion of th e epithelium of the mammary lobul es: Aden osis, lobul ar neopl asia and sma ll cell carcinoma. Surg . Cl in. N. Amer. 52, 497-524 (197 2 ) H aagensen, C. D ., La ne, N ., Latt es, R., and Bodian, c.: Lobul ar neopla sia (so-called lobula r carc inoma in sit u) of th e breast. Cancer 4 2 , 737-769 (1978) Jensen, H., and Schiedt, T. : Str omal response in breast carc inoma and fibr oadenomatosis, estimate d by the aid of th e Alka line Pho sphata se activity. Acta path. microbiol. scand. Sect. A 79, 32 1- 329 (197 1) K raus, F. T., and Neubecker, R. D. : Th e di fferenti al diagnosis of papill ar y tumors of the brea st. Cancer I5 , 444-4 55 (1962) Lambird , P. A., and Shell ey, W. M. : Th e spati al distribution of lobul ar in situ mamm ar y carcinom a. ]. Amer. med . Ass. 210, 689- 69 3 (1969) Lud wig, A. S., Okagaki, T., Richart, R. M., and Lattes, R.: Nuclear DNA content of lobular carcinoma in situ of the breast. Cancer 3I, 1553- 1560 ( 1973) McD ivitt, R. W., Hutter, R. V. P., Foote, F. W., and Stewart , F. W.: In situ lobular carcinoma : A prospective follow-up study indicating cumulative patient risks. J. Amer. med. Ass. 20I, 82-8 6 (1967) Millis, R. R., and Thynne, G. S. ].: In situ intraduct carci noma of the breast: A long term follo w-up stud y. Brit. J . Surg. 62, 957- 962 (1975 ) Murad , T. M., and Scar pelli, D. G.: Th e ult ra stru ctu re of medullary and scirrhous mammary duct car cinoma. Amer. ]. Path. 5°, 335- 345 ( 1967) Mur ad , T. M.: Ultrastru ctu re of ductular carcinoma of the breast (in situ and infilt ra ti ng lobu lar carcinoma) . Cancer 27, 18- 28 (1971) Oz zello, L. : Th e behavior of basement membranes in intra ducta l carc inoma of the breast. Amer. ]. Path. 35, 887-899 (1959) Ozzello, L., an d San pit ak, P.: Epithelial-stromal jun ction of int rad ucta l carcinoma of the breast. Cancer 26, 1186-1198 (1970) Ozzello, L.: Ultra stru cture of intraepithelial carcinomas of th e breast. Cancer 28, 15081515 (197 1) Rosen, P. P., and Lieberman n, P. H .: Lobular carcinoma in situ: Prel imin ary results of a long term follo w-up stu dy, in : "Early di agnosis of breast ca ncer. Methods and result s", Ed. E. Gr und mann and L. Beck, pp, 119- 128. (Ca ncer Campaign, Vol. 1.) Gustav Fischer, Stuttgart-New York (1978) Sachs, H .: Zyrophoromerri sche Unt ersuchun gen bei Prakanzerosen der Mamma. Beitr . path. Anat. I43, 360-377 (1971) Schafer , A., and Bassler, R.: Vergleichende elekrronenmikroskopi sche Untersuchungen am Drii senepithel und am sog. Iobul aren Carcinom der Mamma. Vir chows Arch. Abr, A path. Anal. 346,269-286 (1969) Silverberg, S. G., and Chitale, A. R.: Assessment of significance of pr oportions of intraductal and infiltrating tumor grow th in ductal carci nom a of the brea st. Cancer ]2, 830- 837 (1973) Smith , c.: Carcinoma in situ . Hum . Path . 9, 373-374 (1978 ) Stewart, F. W.: Tumors of the breast. Atlas of Tumor Pathology Sect. I X , fa sc, 34. Armed Forces Institute of Pathology (1950) Toews, H . A., Kata yam a, K . P., Masukawa, T., and Lewison, E. F.: Chromosomes of benign an d mali gnant lesions of th e breast. Canc er 22, 1296- 13°7 (1968) Westbr ook, K. c., and Gallager, H. S.: Intradu ctal carcinoma of the breast. A compa ra tive study . Amer.]. Surg. I30 , 667- 670 (197 5)
414 .
J. A. And ersen
and T . Schiedt
Wheeler, J. E., Enterline, H. T., Roseman, J . M., Tomasulo, J. P., McIlvaine, C. H., Fitts, W. T. , and Kirshenbaum, ]. : Lobular car cinoma in situ of th e brea st : Long term follow-up. Can cer 34, 554-563 (1974)
Received and accepted Januar y 31, 1979
Key words: Breast cancer - Lobular carcinoma in situ - Ductal carcinoma in situ - In traductal carcinoma - Carcinoma in situ Johan A. Andersen, M.D., Chief Pathologist, In stitute of Pathology, Centralsygehuset, DK-6700 Esbjerg, Denmark