ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 9, No. 2 Copyright © 1979, Institute for Clinical Science, Inc.

The Pathological Classification of Human Mammary Carcinoma: Past, Present and Future*

PAUL PETER ROSEN, M.D.

Memorial Hospital for Cancer and Allied Diseases, Memorial Sloan-Kettering Cancer Center,

New York, NY 10021

ABSTRACT

The current classification of mammary carcinoma combines pathological and clinical inform ation in order to define prognostically significant categories. Basic structural features are the anatomic unit of origin, either duct or term inal duct-lobule complex, and the presence or absence of inva­sion. Approximately 90 percent of carcinomas appear to arise from ducts. About one-fifth of invasive duct carcinomas have a better than average prognosis and d istinct light microscopic structural patterns. Future study of biochem ical markers may perm it further refinem ent of the existing classifi­cation of breast carcinoma and lead to the identification of new prognos­tically significant categories in the heterogeneous group currently referred to as “ ordinary” infiltrating duct carcinoma. However, a conservative ap­proach should be adopted toward altering or abandoning the existing clas­sification of breast carcinoma on the basis of immunocytochemical studies until there is an adequate opportunity to determ ine which, if any, markers are truly clinically relevant.

Introduction

To introduce the topic of breast car­cinoma classification, two opinions are related about the classification of human tumors in general.

The first commentary came from a pro­fessor of pathology who practiced diag­nostic pathology for several decades and who was also an accom plished laboratory in v es tig a to r. H e has su g g e s te d th a t pathological classifications were created to be changed and that this was an im­

* Supported in part by contract N01-CB-63997, National Cancer Institute.

p o rtan t ac tiv ity for the investiga tive pathologist to pursue. By changing the re la tionsh ips am ong d ifferen t lesions or by in tro d u c in g new term ino logy , pathologists could “ stay in business.” All that was necessary was to make changes often enough to keep one’s colleagues, especially those in clinical m edicine, in a state of confusion.

A less cynical opinion was rendered recently by Dr. William Russell in his 1978 Ward Burdick Lecture38 when he observed that “a seven-fold increase in the past 25 years in identifiable mor­phologic types of tum or has perm itted

0091-7370/79/0300-0144 $02.00 © Institute for Clinical Science, Inc.

C LA SSIFIC A TIO N O F HUM AN MAMMARY CARCINOM A 145

m ore appropriate irradiation, surgery, chem otherapy and immunotherapy. This has reinforced the importance of and de­pendence upon the pathologist’s diag­nosis of the precise histologic type of cancer.”

Cursory inspection of the current scene in tumor pathology suggests that there is an elem ent of truth in both observations. Yet, in some areas our “ m odern” classifi­cation has changed relatively little from that pu t forth decades ago. The patholog­ical classification of b reast carcinom a originally developed in the 1940’s by Stewart and Foote9,44 is still w idely used w ith little modification throughout the U nited States21 and abroad. To a consid­erable extent, they were able to define most of the clinically significant m or­phologic variants o f b reast carcinom a which could be identified by ordinary light microscopy. Furtherm ore, the rela­tively simple anatomic framework w ithin w hich the lesions w ere arranged pe r­m itted expansion and modification with­out a major rearrangem ent of their class­ification.

U ntil a decade ago the same m ight almost have been said for the field of m alignan t lym phom as a lthough some background unrest was evidently pres­ent. Now, as a resu lt of observations based on light and electron microscopy and cell surface markers, the terminology in th is area has been res tru c tu red so rapidly that even the m ost sophisticated investigators have difficulty understand­ing each other and both the practicing pathologist and clinician are bew ildered by an array of changing terms.

Are we better off w ith the conservative, w ell established classification used for b rea s t carcinom a? W ould it be m ore stim ulating to try out new terms every year?

In my opinion, neither option is ideal or even preferable. Any tumor classifica­tion serves as a means of describing and communicating about the heterogeneity

of neoplastic processes. The definitions of categories are arbitrarily determ ined by the m ethod of descrip tion and the characteristics we choose to emphasize as being meaningful.

Pathological classification by and large has tended to emphasize microscopic fea­tures of tumors and to correlate the struc­tural observations w ith clinical behavior or prognosis. The combination of a dis­tinctive morphological pattern and pre­dictable clinical activity defines the most c lin ica lly u sefu l ca tegories o f b reas t neoplasms. Thus, the precise pathological classification of tumors has considerable potential importance for clinical practice. R ecom m endations for chan g in g t e r ­minology m ust take this into careful con­sideration. It is important to distinguish betw een proposed changes of classifica­tion based on theoretical considerations and those in which long term study has provided an opportunity for an entity to mature.

Past and Present Classifications

B reast carcinom as are read ily su b ­divided on the basis of two major features:(1) the anatomic unit of origin, that is duct or terminal duct-lobular complex and (2) presence or absence of invasion. Further pathologic subclassification is dependent on the coincidence of morphological pat­terns, identified by gross inspection and by microscopic examination. By and large, no type of carcinom a is specifically de­fined by any single morphological feature. It is a particular combination of these fea­tures that is diagnostic and leads us to distinguish one type of carcinoma from another.

Most subcategories are infrequent var­iants by infiltrating duct carcinoma and they generally have a more favorable prognosis than “ ord inary” infiltrating duct carcinoma. The relative frequencies o f the types of b reast carcinom a vary somewhat from one series to another. Fac­

146 RO SEN

tors such as the circumstances of diagnosis (detection by screening vs. general hospi­tal referrals) or country in which data were com piled32 influence the frequency of the types of carcinoma.

In our experience (table I), nearly 10 percent of carcinomas have been non- invasive, originating in either ducts (fig­ure 1) or lobules (figure 2). These patients are essentially 100 percent curable by total mastectomy. Recent studies have de­fined the risk of subsequent invasive car­cinoma after biopsy if no other treatm ent has b e e n g iven .34,36 After an average follow-up of 24 years for 99 patients with lobular carcinoma in situ , subsequent car­cinoma was observed in 30 percent, w ith the risk equally divided betw een both breasts. That is, half of the patients had subsequent cacinoma in the ipsilateral breast and half only in the contralateral breast. An average follow up of 18 years for 15 women w ith untreated intraductal ca rc inom a rev e a le d su b se q u e n t c a r­cinoma in 53 percent, all lim ited to the same breast.

Another 15 to 20 percent are specific variants of invasive duct carcinoma that have an especially favorable prognosis. This group includes m edullary ,30 col-

TABLE I

H is t o lo g ic a l C la s s i f i c a t io n o f Mammary Carcinoma*

N u m berP e r c e n t

T o t a l

NON-INVASIVEIntraductal 48 5I n s i t u lobular 36 4

INVASIVEDuct 619 66Lobular 82 9Medullary 80 9Minimal invasive duct 28 3Colloid 17 2Tubular 14 1Papillary 5 <1Adenoid cystic 1Other 11

Total 941

*Based on a consecutive series of women treated at Memorial Hospital from 1976 to 1978 and reviewed by the author.

loid,22 tubular,45 papillary6 and adenoid cystic28 carcinomas (figures 3 to 7). Each o f these types of tumors has a less than average likelihood of axillary m etastases at the tim e of diagnosis. A more favorable survival is generally observed even when axillary metastases are present. Colloid carcinoma is an exception in this regard, for once axillary metastases occur in pa­tien ts w ith colloid carcinom a, they no longer seem to have a more favorable prognosis.

Invasive lobular or small cell carcinoma (figure 8) accounts for a small proportion of the total. This type of carcinoma oc­curs most frequently in postm enopausal women. In some instances, it is associated w ith coex istan t lobu lar carcinom a in situ .25 The exact histological definition of this type of carcinoma is among the least accurate of all subcategories, and this may account for reported differences with respect to prognosis. In our experi­ence, infiltrating lobular carcinoma has essen tia lly the sam e prognosis w hen compared on the basis of stage as ordi­nary infiltrating duct carcinoma.

Future Prospects

An im portant benefit of the existing classification is that it rem inds us that breast carcinoma is a very heterogeneous disease35 morphologically and clinically. W hile many im portant manifestations of this variability can be identified structur­ally with the light microscope, all have been im pressed by the limitations of this approach, particularly for that large group of tumors classified as “ordinary” infil­trating duct carcinoma (figure 9). Clearly, no t all in filtra ting duct carcinom as of equal size and lymph node status have the same prognosis. It is especially in this group of lesions that additional morpho­logical indicators of prognosis have been sought. Some of these are tumor contour, lymphocytic reaction in tumor, nuclear cytology, vascular invasion and tumor dif-

C LA SSIFICA TIO N O F HUM AN MAMMARY CARCINOMA 147

F ig u r e 1. (A) Intraduc­ta l carcinom a that fea­tures an orderly arrange­ment of small cells ar­ranged in interlacing cords or “bridges.” This pattern is sometimes re­ferred to as “low grade” or “ w ell differentiated” intraductal carcinoma. All types of intraductal carci­noma are 100 percent cureable by total mastec­tomy. The prognostic sig­nificance of patterns in untreated intraductal car­cinoma in unknown. Hem­atoxylin and eosin, x 220.

F ig u r e 1. (B) Comedo type o f intraductal carci­nom a. D uct lum en is filled w ith neoplastic cells. The central necrotic material often calcifies. Because the calcified de­tritus may be seen in mammograms, this type of carcinoma is especially lik ely to be detected radiologically in the ab­sence of a palpable tumor. In rare instances, aggre­gated ducts filled by in­traductal carcinoma may produce a mass. Hema­toxylin and eosin, x 141.

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C LA SSIFICA TIO N O F HUM AN MAMMARY CARCINOM A 149

fe re n tia tio n . U n fo rtu n a te ly , m any of th e se c h a ra c te r is tic s are d iff ic u lt to m easu re q u a n tita tiv e ly and thus are highly subjective observations suscepti­b le to c o n s id e rab le in te r-a n d in tra ­observer variation. Consequently, there appears to be little chance that these fea­tures can be reliably incorporated into a useful classification of breast carcinoma.

O ur knowledge is especially lim ited with respect to prognosis in patients with infiltrating duct carcinoma who do not have ax illary m etastases. T he recen t dem onstration of a significantly poorer prognosis for patients w ithout axillary m etastases w ho have in tra ly m p h a tic tumor emboli in the breast around the primary lesions2 suggests that new av­enues of study rem ain to be pu rsued along these traditional lines.

However, other methods of describing and c lassify ing the h e te ro g e n e ity of breast carcinoma may w ell prove more productive in the future. Relatively new techniques for identifying many secre­tory and metabolic products of tumor cells are now readily available for investiga­tive use. In contrast to the purely struc­tural classifications of carcinomas which dom inated the field for decades, there is a growing appreciation of the varied sub­stances that breast carcinoma cells pro­duce. T h is may u ltim a te ly lead to a biochemical or functional classification of breast carcinoma or at least add this di­m ension to the existing classification.

4-----------------------------------

Histochemical stains for mucins, mela­nin, bile and other substances have been in the pathologists armamentarium for a long time. However, technical advances in immunohistochemical methods, radio­immunoassay and other procedures now make it possible to define a spectrum of cellular products or markers which were until recently not known to be present in or associa ted w ith b reas t carcinom a. Some of the markers listed in table II have been m easured in the blood as a means of following the course of disease and anticipating metastases.3,40,34' 46 Car- cinoembryonic antigen and human cho­rionic gonadotrophin have been most in­tensively studied in this respect. Others, such as estrogen receptor protein (ERP), have been assayed in tumor tissue and used to predict responsiveness to therapy for recurrent disease.14

The analysis of markers in peripheral blood or in homogenized tumor tissue is clinically useful bu t provides little in­formation about the production and dis­tribution of m arker substances w ithin individual breast carcinoma cells. It is already known that a substance such as mucin is not detectable in all cells of an adenocarcinom a and the sam e is ex­pected to be true of other cellular prod­ucts. There is considerable evidence that ERP is not uniformly present in all tumor cells. Differences have been observed by us in the distribution of ERP among some of the traditional subcategories of breast

F igure 2. Lobular carcinoma in situ is a microscopic type of pre-invasive carcinoma that does not produce clinical symptoms and is not readily detected by mammography. Acini that compose the lobule are filled with a population of small, uniform neoplastic cells. Acinar distension is not prominent in the example shown here. Hematoxylin and eosin, x 375.

F igure 3. Medullary carcinoma, an invasive duct carcinoma, forms a well circumscribed palpable mass. When under 4 cm in diameter, it is likely to be fleshy and solid; larger examples tend to be cystic. Micro­scopically, the tumor cells are arranged in broad zones separated by stromal septae. A dense infiltrate of lymphocytes and /or plasma cells is seen in the stroma within or around the tumor and may also be dispersed among the carcinoma cells. Despite an anaplastic cytologic appearance, typical examples of this tumor have a relatively favorable prognosis. Variants of infiltrating duct carcinoma with some but not all features of typical medullary carcinoma (so-called atypical medullary carcinoma) have a less favorable prognosis. Fewer than 20 percent of typical medullary carcinomas have been estrogen receptor positive by the dextran-charcoal method. Hematoxylin and eosin, x 145.

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carcinoma.34,35 Thus, low levels of ERP have been found consistently in m edul­lary carcinom a. Almost all in filtrating

F ig u r e 4. Colloid (gel­atinous) carcinoma, a var­iant of invasive duct car­cinom a, tends to be grossly circum scribed and gelatinous in consist­ency. Favorable progno­sis is characteristic for those cases in which the tumor is at least 75 per­cent gelatinous. As the proportion o f ordinary in­filtrating duct carcinoma increases, the frequency of m étastasés increases and the prognostic advan­tage dim inishes. Micro­scop ically , clusters o f sm all, uniform tumor cells are found in pools of extracellular m ucinous secretion w hich consti­tutes the pale background in this illustration. In our experience, pure colloid carcinoma tends to be es­trogen receptor negative by the dextran charcoal method. Hematoxylin and eosin, x 292.

F ig u r e 5. Tubular car­cinom a, a w e ll d iffer­entiated variant o f infil­trating duct carcinom a usually forms a stellate mass less than 2 cm in diameter. Calcification in the stroma or tumor glands and a small mass make this one small inva­sive lesion likely to be de­tected by mammography before it is palpable. Mi­croscopically , the n eo ­plastic c e lls and the glands they form closely resemble non-neoplastic mammary ducts (arrow). Tubular carcinoma tends to be estrogen receptor negative by the dextran charcoal method. Hema­toxylin and eosin, x 130.

lobular carcinom as have had substan ­tially higher levels of ERP. Variability in ERP content also occurs betw een spa-

CLA SSIFIC A TIO N O F HUM AN MAMMARY CARCINOM A 151

F igure 6. Cystic papil­lary carcinom a usually forms a w ell circum ­scribed mass. Fronds of fibrovascular stroma sup­port the neoplastic cells in this illustration. The fibrous wall, often found in this lesion, is seen in the lower part of the il­lustration. Hematoxylin and eosin, x 140.

F igure 7. A denoid cys­tic ca rc inom a , an ex­tremely rare variant of in­filtrating duct carcinoma, is a grossly invasive tumor. M icroscopically, the pattern resembles le­sions seen in the salivary glands and skin adnexa. M etastases occur infre­quently and even when present in axillary lymph nodes dissem ination is unusual. H em atoxylin and eosin, x 140.

tially separate tumor deposits s im ultane­ously and be tw een temporally separate sam ples of tu m o r33 o b ta in ed from the same patient.

A s im ila r o b se rv a t io n has b e e n r e ­p o r te d for th e d is t r ib u t io n o f c e r ta in po lypep tide hormones in small cell car­cinoma of the lung.1 This phenom enon

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Figure 8. Infiltrating lobular carcinoma may occur as a single palpable mass or as numerous almost imperceptible nodules throughout the breast. Microscopically, the tumor cells are small and are typically arranged in strands, the so-called “ Indian file” pattern (straight arrows). In this photo-micrograph, persisting in situ lobular carcinoma is also present (curved arrows). Nearly 90 percent of infiltrating lobular carcinomas prove to be estrogen receptor positive when studied by the dextran charcoal method. Hematoxylin and eosin, x 140.

applies to the production of most “ mar­kers” in neoplastic cells, including sub ­stances such as “m ucin” and m elan in that are dem onstra ted by commonly available histochemical procedures. Immunofluo- rescent s tudy of breast carcinomas has confirm ed the he te ro g en eo u s d is tr ibu ­tion of ERP in tumor cells.18,27

R ecently , a repo rt has l inked tissue lev e ls o f E R P w i th p ro g n o s is .17 T h e prognosis for those in the ERP positive group was more favorable than for the E R P n e g a t iv e p a t ie n ts . O th e r d a ta s u g g e s t a h ig h e r r e s p o n s e ra te to cytotoxic chemotherapy among patients w ith low or a b se n t E R P v a lu e s ,19 a l­though this has b een d isp u ted 39 and re­mains an unresolved question.

Few studies have been carried out re ­lating the cellular distribution of marker substances to stage of disease or to prog­nosis. O ne exception is a report by Wal­

ker49 who stud ied the distribution of the alpha subun it o f hum an chorionic gonad­otrophin in 53 specim ens of breast carci­nom a. U s in g an im m u n o p e ro x id a s e technique , clusters of positive staining cells were de tec ted in 12 cases (22.6 per­cent) including nine of 34 infiltrating car­c in o m as . A m o n g ca ses w i th ax il la ry lymph nodes available for study, metas- tases were p resen t in 8/11 (72 percent) with the alpha subunit and in 14/33 (42 percent) w ithout the marker.

The light microscopic study of morpho­logic p a t te rn s asso c ia ted w ith m arker substances has received little attention. It is possible that the derepression of gen ­etic information presum ably responsible for the production of a marker may, in c e r ta in in s ta n c e s , a lso in f lu e n c e the growth pattern of a tumor, perhaps by genetic linkage. At least one preceden t for an association of altered morphologic

CLA SSIFICA TIO N O F HUM AN MAMMARY CARCINOMA 153

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154 ROSEN

T A B L E II

Biochemical Markers Associated with Mammary Carcinoma

Method of D e t e c t i o n HC EM TA PB other

ERP18'27 t3 3 xCEA13,23,43 (x) (x)hPL42Alpha-anti-trypsin2 9,1+7 (X)Alpha-subunit HCG1*9 XBeta-subunit HCG2 '24'41 XCalcitonin3,11'15 (X)

Norepinephrine1 X XNeurosecretory granules5 X XIsoferritin2®Lactoferritin13'37 XCasein7'13 XSecretory component1® X

Abbreviations: HC = histochemical; EM = electronmicroscopy; TA = tissue assay; PB = peripheral blood; ERP = estrogen binding protein; CEA = carcinoembry- onic antigen; hPL = human placental lactogen;HCG = human chorionic gonadotrophin; (X) = tissue localization reported in tumors other than breast carcinoma.

pattern and ectopic hormone production exists in the choriocarcinomatous form of gastric adenocarcinom a.8 W ell doc­um ented transitions betw een typical car­cinom atous and choriocarcinom atous e lem en ts have b een observed in the stomach with the production of HCG by the latter component.

One recently described histopatholog- ical marker in mammary duct carcinoma, the formation of neurosecretory granules or of no rep ineph rine ,5,16 has been as­sociated w ith a light microscopic growth pattern resem bling carcinoid tumors that originate in other organs. An intraductal component can often be found that may be either papillary or solid and is other­wise indistinguishable from the intraduc­tal com ponent of carcinomas not charac­terized by neurosecretory granules. It is noteworthy that not all breast carcinomas with neurosecretory granules have a car­cinoid pattern. The prognosis for duct carcinoma with neurosecretory granules appears to be no better than for ordinary infiltrating duct carcinoma. In the ab­sence of a confirmed unique cell origin48

or of distinctive clinical features, it is ap­propriate to consider this a morphologic variant of duct carcinoma (intraductal and infiltrating duct carcinoma with neurose­cretory granules). To do so does not de­tract from the value of the observation nor does it lim it the opportunities for future study and definition of the lesion.

Conclusion

W hile the possibilities for future study in this field are stimulating, it is appro­priate to take a conservative attitude to­ward altering or abandoning our existing classification of breast carcinomas. It is conceivable that the m ultiplicity of sub­stances produced by some tumors will defy easy categorization. The addition of term s based on the dem onstra tion of marker substances will prove more useful if there is an opportunity for prospective study. Only in this way will it be possible to determ ine which, if any, of the new “m arkers” are truely clinically relevant and should be specifically designated in the classification. In other organ systems it has been customary to have a chaotic expansion of terminology over a num ber of years followed by a period of consoli­dation usally featuring one or more inter­national conferences on nom enclature to sort out the confusion. My hope is that this m ight be avoided with respect to the classification of breast cancer since as pathologists we have to live with the clas­sifications that we create.

Addendum

Two relevant studies that reinforce the conclusions of our report have come to attention since this paper was subm itted for publication. G oldenberg et a l1 de­scribed localization of CEA activity in a mammary carcinoma using an immuno- peroxidase m ethod. Cohle et al2 have detected m em brane-bound cytoplasmic granules that reacted with anti-ACTH serum in the cells of a mammary adeno­

XX X

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C LA SSIFIC A TIO N O F HUM AN MAMMARY CARCINOM A 155

carcinom a. T h is p a tie n t also had increased serum levels of ACTH and symtoms referable to hypercorticism.1. G o l d e n b e r g , D. M., Sh a rkey , R. M., and

Prim us, F. J.: Immunocytochemical detection of carcinoembryonic antigen in conventional histopathology specimens. Cancer 42:1546- 1553, 1978.

2. Co h l e , S. D ., T sc h en , J. A., Sm ith , F. E., La n e , M., and McG a vr a n , M. H.: ACTH- secretin g carcinom a o f the breast. C ancer (In press).

Acknowledgm eiit

Thanks are extended to Ms. Lynn Flynn, who as­sisted in the preparation of the manuscript, and to Mrs. Margaret Uibel, Medical Photographer, D e­partment of Pathology, who prepared the photomi­crographs.

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to n , J, C., Me n d e l so h n , G., Be a v en , M. A., Ab e l o f f , M.D., and E t t in g e r , D. S.: Variable content of histaminase, L-DOPA carboxylase and calcitonin in small-cell carcinoma of the lung. New Eng. J. Med. 229:105-110, 1978.

2. B r a u n s t e i n , G. D., V a i t u k a i t i s , J. L., C a r ­b o n e , P. P., and ROSS, G. T.: Ectopic produc­tion of human chorionic gonadotrophin by neoplasms. Ann. Int. Med. 78:39-45, 1973.

3. Coom bes, R. C., Ea sty , G. C., D e tr e , S. I., H ill yard , C. J., St e v e n s , I., G irgis, S. I., Ga la n te , L. S., Hey w o o d , L. Ma c In tyr e , I., and N ev ille , A. M.: Secretion o f immunoreac- tive calcitonin by human breast carcinomas. Brit. Med. J. 4:197-199, 1975.

4. Coom bes, R. C., Ga z e t , J. C., Sloan , J. P., Po w les, T. J., F ord , H. T., La u r e n c e , D. J. R., and Ne v il l e , A. M.: Biochemical markers in human breast cancer. Lancet 2:132-134, 1977.

5. C u b i l l a , A. L. and W O O D R U FF, J. M.: Primary carcinoid tumor of the breast. Amer. J. Surg. Path. 2 :283-291, 1978.

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