Histologic variants of infiltrating lobular carcinoma of the breast

H I S T O L O G I C V A R I A N T S OF INFILTRATING LOBULAR C A R C I N O M A OF T H E B R E A S T Robert E. Fechner, M.D.*

Abstract T h i r t y - e i g h t breasts with lobular Carcinoma in situ a n d an additional intraductal o r infiltrating cancel- were studied. Twenty-six o f the additional cancers were d i a g n o s e d as infiltrating lobular c a n c e r on the basis o f a single p o p u l a t i o n o f small u n i f o r m cells cytologically identical to those in lobular c a r c i n o m a in situ. In 20 o f these cases the Conventional p a t t e r n o f infiltrating lobular c a n c e r was evident with an i n d M d u a l cell infiltrate with foci o f single filing. Ill the o t h e r six t h e r e was a confluelit a r r a n g e m e n t o f cells in solid sheets. This pattern has not b e e n previously r e p o r t e d as a p a t t e r n o f infiltrating Iobular cancer. Because o f the identical cytologic a p p e a r a n c e , we believe it is a variant o f infihrating Iobular cancer a n d should be diagnosed as such.

T h e morpholog)" o f infiltrating lobular c a r c i n o m a has b e e n illustrated on n u m e r o u s occasions in r e c e n t years with r e p e a t e d e m p h a s i s on the single file a r r a n g e m e n t o f small neoplastic cells? -3 H o w e v e r , a n o t h e r pattern o f infiltration characterized by conttuent nests o f cells is seen in s o m e patients with lobular carcin o m a in situ. T h i s can occur in association with single filing or it can be the sole pattern. Ill tile latter situation the lesion m a y not b e recognized as Iobular carci-

noma. It is tile p u r p o s e o f this discussion to describe six infiltrating carcinomas ill which the p r e d o m i n a n t pattern was large confluent nests o f cells cytologically identical to those in the lobular c a r c i n o m a in situ that was present.

MATERIAL A N D METHODS T h e files o f the Surgical Pathology Service at T i l e Methodist Hospital contain

*Professor of Pathology and Director of Surgical Pathology and Cytology, University of Virginia School of Medicine, Charlottesville, Virginia.

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HUMAN PATHOLOGY--VOLUME 6, NUMBER 3 May 1975 38 cases o f lobular carcinoma in situ with invasive carcinoma or intraductal cancer. T i m diagnosis o f lobular carcinoma in situ was m a d e when the cytologic and bistologic criteria e n u m e r a t e d elsewhere were fidfilled? T h e characteristics o f the invasive c o m p o n e n t were tabnlated as to both cytologic features and pattern o f infiltration. C a s e s were classified cytologically as infiltrating lobular carcinoma w h e n the entire im'asive c o m p o n e n t consisted" o f small u n i f o r m ceils with nuclear and Cytoplasmic features identical to those o f Iobular carcinoma in situ. Lesions were classified as infiltrating ductal cancer when the cells were larger and m o r e p l e o m o r p h i c than those o f infiltrating lobnlar carcinoma. T w o patterns o f "infiltration were identified: tim individual cell pattern and the confluent pattern. T h e individual cell pattern consisted o f ceils haphazardly scattered in fibrons s t r o m a a n d frequently f o r m i n g single f i l e s - t h e classic infiltrating lobular cancer. T h e ' c o n f l u e n t pattern was f o r m e d by cells a r r a n g e d in irregularly slmped solid nests. Such nests were sometimes in continuity with a single file pattern o f cytologically identical cells. T h e large extralobular dncts were e x a m i n e d for intradnctal carcinoma, which was classified on the basis of pat2 tern into solid, cribriform, papillary, or comedocarcinoma. Specimens from the solid, cribriforxn, attd papillary lesions were all c o m p o s e d o f small u n i f o r m cells cytologically identical to tltose seen in l o b u l a r carcinoma in sitn, a l~henomenon that has been illustrated in detail? T h e c o m e d o c a r c i n o m a s were composed o f large p l e o m o r p h i c cells with fi'equent mitoses and central necrosis; these were cytologically distinct fi'om the small cell cancers, as comparative illustrations fi'om o u r material have already shown. 6

RESULTS

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F o u r o f tire 38 breasts had intraductal cancer in the inajor ducts as tile only carcinoma in addition to the lobular carcinoma in situ. T h r e e were large cell, p l e o m o r p h i c coinedocarcinomas with :inticli necrosis. T h e y were cytologically qnite different f r o m the lobular carcinoma in situ. T i m

f o u r t h intraductal cancer was papillary, consisting o f small uniform cells cytologicall).' similar to those in Iobular carcin o m a m situ. This neoplasm was not n e c r o t i c a n d was the type o f lesion coexisting with lobular cancer that Ires been illustrated in a previous communication. ~ Infilirating carcinoma was present in 3,t breasts (Table 1). T h r e e were tubular (well differentiated) carcinoma in which t h e well defined dncts were the only comp o n e n t in the infiltrating cancer. T h e s e neoplastic ducts were clmracterized by a single layer o f cells, some o f wltich had a p o c r i n e "snouts. ''z T w o breasts had infiltrating papillary cancers with small nests o f cells and well defined ductal structures intermixed. T h e s e recapitulated the cribrif o r m p a t t e r n o f the intraductal papillary cancer, which was also present. In two cases classified as infiltrating ductal cancer the tissne consisted o f irregular nests and cords o f cells that were larger and m o r e p l e o m o r p h i c than those in lobular carcin o m a in sltu. In one case t h e r e was a mixture o f infiltrating lobular and infihrating ductal cancer. About 30 per cent o f the t u m o r consisted o f small u n i f o r m ceils infiltrating p r e d o m i n a n t l y in a single file pattern. T h e major portion o f the t u m o r consisted o f cells with a larger p l e o m o r p h i c cell population typical o f infiltrating ductal cancer. T h e r e were 26 cases in wltich the infiltrating c o m p o n e n t was a m o n o m o r p h i c population o f small u n i f o r m cells. In terms o f pattern tlte infiltrating c o m p o n e n t consisted p r e d o m i n a n t l y o f tim individual cell pattern i n 20 breasts. Eight o f tttis

T A B L E 1. TYPES OF CANCER ASSOCIATED WITU LOBULAR CARCINOMA IN SITU i. Infiltrating Lobular Typical Variant Tubular Ductal l'apillary Mixed

20 6 3 2 2 1

II. lntraductal (extralobular ducts) Small cell (papillary, solid, cribriform) 20* l.arge cell (comedocarcinoma) 3

*All except one also had infiltrating lobular cancer or infiltrating papillary cancer.

I N F I L T R A T I N G LOBULAR CARCINOMA OF T H E BREAST--FEcn,X~R

Figure I. Sharply circumscribed nests of uniform small cells characterize a variant form o[ infiltrating Iobular carcinoma. (I-tematoxyliil and eosin stain, x 40.)

g r o u p h a d a few small islands o f confluent cells a n d an occasional tubtfle, but these n e v e r constituted m o r e t h a n 5 p e r cent o f the t u m o r , a n d t h e r e f o r e they are considered as e x a m p l e s o f the typical g r o u p o f infiltrating lobular carcinomas. T h e r e m a i n i n g six breasts were classified into the variant g r o u p o f infiltrating lobular c a r c i n o m a s a n d h a d a p r e p o n d e r ance o f the confluent pattern. T h e y could be f u r t h e r divided into two groups. In three cases the confluent p a t t e r n was the sole c o m p o n e n t o f infihration a n d was characterized by compact, sharply circumscribed nests o f cells (Figs. I, 2). T h e s e three cases also s h a r e d the c o m m o n feature in h a v i n g a dense, focally hyalinized stroma. T h e o t h e r t h r e e cases included a single file infiltrating p a t t e r n but had a p r e p o n d e r a n c e o f confluent cells (Fig. 3). T h e s e nests were s o m e w h a t less sharply defined a n d less c o m p a c t t h a n those o f the previous g r o u p (Figs. 3, 4). T h e adjacent fibrous s t r o m a was sparse a n d not hyalinized. T h e individual cell p a t t e r n o f infiltration m a d e tip a b o u t 5 to 10 p e r cent o f the infiltrating c o m p o n e n t . T h e s e cases were all characterized by a conspicuous

epithelial p r o l i f e r a t i o n in the e x t r a l o b n l a r ducts.

Clinical Results A n u m b e r o f clinical features were reviewed a n d s o m e are s u m m a r i z e d in T a b l e 2. T h e a g e r a n g e is b r o a d e r in the typical g r o u p , but this is probably only a function o f a g r e a t e r n u m b e r o f cases, since the m e d i a n a g e o f 53 years d o e s not s e e m significantly different f r o m the m e d i a n age o f 47 in the variant g r o u p . In six o f the 90 typical cases the patients were l~remenol)ausal; this was tl~e case in two o f the six variant cases. F o u r o f the 14 postm e n o p a u s a l w o m e n o f the typical g r o u p were taking P r e m a r i n but n o n e o f the variant g r o u p were, a h h o u g h no definite s t a t e m e n t either positively or negatively was obtainable in five o f the typical g r o u p a n d in one o f the variant group. All e x c e p t two patients in the typical g r o u p w e r e t r e a t e d by radical or modified radical mastectomy. In the two exceptions the patients had simple mastectomies since clinical evidence o f b o n e metastases were present. T h e f r e q u e n c y o f n o d e metastases is given in T a b l e 2.

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Figure 2. Higher magnification o f the uniform cells o f infiltrating carcinoma seen in Figure I. Cells are cytologically identical to those o f Iolmlar carcinoma in situ. (.lt lematoxylin a n d eosin stain. • 420.)

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Figure 3. A conventional pattern o f infiltrating Iobular carcinoma is seen ;it right and areas oFconfluent infihration at left. (Hematoxylin and eosin st,tin. • 160.)

INFILTRATING LOBULAR CARCINOMA OF T H E BREAST--FECllNER

Figure 4. tligher magnification of uniform cells from confluent infihrating component cytologically identical to Iobular carcinoma in situ. (ttematoxylin and eosin stain, x 420.)

DISCUSSION

Tlie association o f lobular carcinoma in situ with different t y p e s o f infiltrating cancer has been r e p o r t e d by several authors, a'8-~~ T i m usual basis for separating invasive lobular cancers f r o m other infiltrating cancers has been the pattern

TABLE 2.

COMPARISONO F CLINICAL A N D I)ATIIOLOGIC FEATURES OF TYPICAL A N D V A R I A N T INFILTRATING L O B U L A R C A N C E R S

Typical

No. of breasts 20 31-85 }'ears Age range Median age 53 Size of lesion (range) 0.5-4.0 cm. 2.0 cm. Median size No. of patients with nodes for histologic exa,ninatio,l 18 Metastases in nodes 8

Variant

6 43-66 years 47 0.7-4.0 cm. 1.5 i:m.

r a t h e r than tlm cytologic feattu'es o f tile infiltrating lesion. We believe that an invasive lesion c o m p o s e d o f small u n i f o r m cells cytologically identical to those o f lobular carcinoma in sitn shonld be classified as infiltrating Iobular cancer r e g a r dless o f the pattern. T h e majority o f infiltrating Iobular cancers will contilme to fall into the convefitiolml pattern o f in filtrating lobular cancer characterized by a Imphazard a r r a n g e l n e n t o f individnal cells with a r e a s ' o f single filing. However, some small cell infiltrating cancers associated with lobnlar carcinoma in situ have a coniluent cell Ibattern with either minimal o r total absence o f a Single file c o m p o n e n t . W h i c h e v e r pattern is assumed,: tim pro:_ ticipating cells have the cytologic featm'es o f the c o n c o m i t a n t lobular carcinoma in sitn, a n d it seems reasonable to consider the infiltrating c o m p o n e n t as infiltrating lobular cancer. We c a n n o t identify any conspicuous clinical differences in the two g r o u p s o f patients in terms o f age or menstrual

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HUMAN PATHOLOGY--VOLUME 6, NUMBER 3 May 1975 status. N o n e o f the six patients in the variant g r o u p had nodal metastases, whereas 10 o f the 20 patients in the typical g r o u p had either regional or distant metastases when the patients were first examined. We do not tlfink that there is an)' significance to the lack o f metastases in a g r o u p o f only six w o m e n , but this deserves f u r t h e r study in additional cases since it may r e p r e s e n t a t r e n d o f biologic importance. Tire major reason for identifying infiltrating Iobular c a n c e r lies in the risk o f bilateral disease, which exceeds that o f infiltrating ductal cancer. Regardless o f w h e t h e r o n e wishes to attack the Second breast immediately a f t e r lobular cancer has been f o u n d in the first, it seems useful to be able to identify a w o m a n wtto is at especially high risk for a second breast cancer. For that reason we are e m p h a sizing the confluent pattern o f Iobular cancer described herein. For the p u r p o s e o f this discussion, patients with confluent infiltrating lobular c a n c e r also had lobular carcinoma in situ. T h e r e f o r e the identification o f lobular carcinoma in situ in the contralateral breast o f two o f six patients with confluent infiltrating lobular cancer is not surprising and is similar t o the synchronous bilateral rate in large series. 8 However, we anticipate tttat patients with the continent pattern o f infiltration described herein and lacking dentonstrable lobular carcinoma in situ will be shown to be at increased risk for bilateral cancer. This s t a t e m e n t is based on the analogous situation whereby patients with typical infiltrating lobular cancer (individual cell pattern) who lack lobular

carcinoma in situ have a high fi'equency o f bilateral breast cancer? Even tltough lobular carcinoma in situ was not f o u n d in the first breast, it was frequently identified in the contralateral breast. T l t e r e f o r e cases o f small u n i f o r m cell infiltrating carcinoma with a confluent pattern should be classified a s infiltrating lobular cancer with a p p r o p r i a t e concern for the second breast.

REFERENCES 1. Newman, W.: Lobular carcinoma of the female breast. Ann. Surg., 164:305-314, 1966. 2. Warner, N. E.: Lobular carcinoma of the breast. Cancer, 23:840-846, 1969. 3." McDivitt, R. W., Stewart, F. W., attd Berg, J. W.: T n m o r s of the breast. In Atlas of T u m o r Pathology. Washingtoq, DC, A r m e d Forces Institute of l'athology, 1968, Second Series, part 2, pp. 63-85. 4. Fechner, R. E.: Infiltrating lobular carcinoma without lobular carcinoma in sitn. Cancer, 29:1539-1545, 1972. 5. Fechner, R. E.: Epithelial alterations in the extralobnlar dt,cts of breasts with lobular carcinoma. Arch. Path., 93:!64-171, 1972. 6. Fechner, R. E.: Ductal carcinoma involving the lobule of the breast: a source of confusion with lobular carcinoma in situ. Cancer, 28: 274-281, 1971. 7. Taylor, H. B., and Norris, H. J.: Well-differentiated carcinoma of the breast. Cancer, 25:687692, 1970. 8. Doneg-an, W. L., and l'erez-Mesa, C. M.: Lobtflar c a r c i n o m a - - a n indication for elective biopsy of the second breast. Ann. Surg., 176:178187, 1972. 9. Haagensen, C. D.: Diseases of the Breast. Ed. 2. l'lfiladelphia, W. B. Sannders Company, 1971, pp. 503-527. 10. Ashikari, R., et al.: I nfihrating lobtdar carcinoma of the breast. Cancer, 31:110-116, 1973. Department of Pathology University of Virginia School of Medicine Charlottesville, Virginia 22903

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