Disseminated Lobular Carcinoma - A Predominantly Pleomorphic Lobular Carcinoma of the Whole Breast

Disseminated Lobular Carcinoma - A Predominantly Pleomorphic Lobular Carcinoma of the Whole Breast

Path. Res. Pract, 166,456-470 (1980) Department of Pathology, City and Academic Hospital, Fulda, West Germany Disseminated Lobular Carcinoma - A Pre...

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Path. Res. Pract, 166,456-470 (1980)

Department of Pathology, City and Academic Hospital, Fulda, West Germany

Disseminated Lobular Carcinoma - A Predominantly Pleomorphic Lobular Carcinoma of the Whole Breast" R. BASSLER and H. KRONSBEIN

Summary Contrary to the usual distribution of lobular carcinoma in situ in a few lobules or terminal ducts, a case of disseminated lobular carcinoma is described occupying all lobules of the whole breast. The tumor developed in the left breast of a 61-year-old woman with the clinical symptoms of an increasing diffuse induration. The proliferating cells were predominantly pleomorphic with hyperchromatic nuclei and loss of cell cohesion. In 690 slides examined the tumor cells in lobules and ducts revealed various stages of proliferation with transition to invasive small cell carcinoma in 15 different areas. This disseminated lobular carcinoma appears to be an advanced form of primary cancer multicentric in one breast and originating from the basal cells of the lobules and terminal ducts due to a general carcinogenic stimulus.

Introduction Lobular carcinoma in situ (LCIS) of the breast is described in detail elsewhere in this issue. Different cell patterns have been noted in LCIS. A mostly uniformly proliferating pagetoid cell type has been noted by Foote and Stewart (1941). Thirty years later Haagensen (1971) distinguished two cell types in this lesion which he called lobular neoplasia. The "A"-type is characterized by uniform small cells within acini and ductules while the "B" -type cells appear pleomorphic and more atypical and malignant. It is not always easy to draw a borderline between the two types. Further histochemical studies have shown that cells of lobular carcinoma are able to synthesize mucopolysaccharides within cytoplasmic vacuoles (the so-called signet-ring cells) or diffusely throughout the cytoplasm (Gad and Azzopardi, 1975; Breslow and Brancaccio, 1976). Citoler and Zippel (1977) ':. Dedicated to Prof. Dr. W. Doerr, Heidelberg, on the occasion of his 65th birthday.

Disseminated Lobular Carcinoma of the Breast . 457

found a correlation between intracellular mucin production and nuclear pleomorphism of the "B" -type cells. During the last four years (1975-1978) 41 out of a total number of 586 breast cancers (7.2%) were found to be LCIS in our institution while 20 cases (3.5%) were recognized as invasive small cell carcinoma indicating one subtype of invasive lobular carcinoma. This report describes the first case of a diffuse form of LCIS occupying all lobules of the entire breast. The tumor belongs predominantly to the "B"-type exhibiting pleomorphism of nuclei with transition to invasive small cell carcinoma in 15 areas. We studied 1.233 lobules which were found in 690 slides of this breast.

Case Report The 61-year-old woman had no family history of breast disease. In November, 1977, a screening examination revealed a diffuse painless induration of the left breast. There was no nipple discharge. The axillary nodes were slightly enlarged. At mammography some scattered microcalcifications were noted in a dense breast tissue without sign of a circumcribed tumor. The patient was admitted to the hospital on December 5, 1977. On physical examination she showed a slight enlargement of the breast and only little retraction of the skin in the lower quadrants at elevation of the left arm. The breast tissue especially in the upper outer quadrant was indurated but no lump was palpable. There was "peau-d'orange" but no retraction of the mamilla. Biopsy A circumareolar incision was made and a piece of tissue was removed from the central area of the breast measuring about 5 em in diameter. The specimen consisted of glandular and fat tissue of white and brownish color and irregular consistency but without nodes or cysts. A cryostat section revealed a lobular and ductular carcinoma in situ and an area with an invasive small cell carcinoma. Paraffin sections confirmed the diagnosis. Therefore a radical mastectomy was performed. Mastectomy specimen The whole breast (19 X 12 X 4 cm) with a biopsy wound (5 ern) was cut into parallel sections (0.5-1 ern). The sections were labeled and show-

458 . R. Bassler and H. Kronsbein

Fig. 1. Section of mastectomy specimen with an area of brownish colored tissue indicating the disseminated lobular carcinoma (surrounded by arrows).

ed a white, gray and brownish tissue surrounded by fat lobules (Fig. r), In the submamillary area small ectatic ducts containing a yellow secretion were noted. A more dense tissue was present in the upper outer quadrant. Lobules or groups of lobules could not be distinguished grossly. No lymph nodes were seen under the pectoral muscle. 8 axillary lymph nodes were free of tumor.

Histological Findings The breast was examined in numerous areas. Skin and nipple exhibited no pathological changes. The biopsy area showed recent hemorrhages. The large submamillarian ducts appeared narrow containing ordinary epithelium. The intraglandular ducts were slightly ectatic and filled with homogeneous secretion. Focally solid intraductal proliferations were evident. In some smaller ducts, especially in the upper outer quadrant, solid intraductal proliferations with occlusion of the lumen were present, sometimes with central necrosis. In some areas small cysts were partially lined by a multilayered epithelium. Apocrine metaplasia was also seen (Fig. 2). Histologically the changes of the lobules are most prominent. Almost all lobules are slightly enlarged and show a cellular atypical epithelium indicating lobular neoplasia with various cell types. Among r,233 examined lobules, only 8 were found to be free of tumor cells. The other lobules show different grades of cell proliferations beginning in the basal layer of the acinar epithelium with development of large clear cells (paget-like) lifting the surface epithelium (Fig. 8). This early stage can be recognized in some lobules. At the next stage, the lobules are filled with uniform cuboidal cells. Their nuclei take a slightly more intense stain but show no mitotic figures. Only a few cells contain droplets of PAS-positive material. These

Disseminated Lobular Carcinoma of the Breast . 459

changes indicate LeIS or the lobular neoplasia type "A" of Haagensen (1971). The number of these lobules is small. The solid cell groups have some gaps, the cell shapes are irregular and show transformations to type "B". These cells dominate in most lobules and have led to confluence of several lobules and to lobular hyperplasia. Stromal edema of the surrounding connective tissue is distinct. The terminal ducts and acini are filled by solidly packed atypical polygonal cells. The intact basement membrane delimits the lesion sharply against the compressed intralobular stroma. The tumor cells lose cohesion and appear as Paget-like single cells containing many PAS-positive cytoplasmic deposits. Cells with intracellular vacuoles containing PAS-positive material (signet-ring cells) are also present. The nuclei are more hyperchromatic but mitoses are rare. With increasing cell proliferation the lobules grow and form macroacini (Fig. 2). These cell proliferations extend to the terminal ducts. Here small uniform (type "A") and polygonal (type "B") cells are found leading to luminal occlusion. Single ducts show central necrobiosis and necrosis like a comedo-type carcinoma. Other extended duct segments are filled with solid or papillary epithelium with or without moderate atypia corresponding to "A"- or "B"-cell types. There are focal changes of a low grade fibrocystic disease, sometimes with intraductal papillomatosis. A few small cysts with apocrine metaplasia are included in the lobular neoplasia. Besides the diffuse lobular carcinoma in situ, there are 15 separate areas in the 690 examined slides showing an anaplastic invasive small-cell carcinoma. Occasionally these foci show adenoid patterns, but the typical small-cell tumor with pronounced stromal infiltration predominates. Serial sections show transitions of acini with polygonal cells to the infiltrating tumor splitting up and dissolving the basement membrane. There is one area with a small focus of a tubulo-lobular carcinoma. In addition intraductal carcinosis localized in peripheral segments was found. The axillary lymph nodes were slightly enlarged and surrounded by fat tissue. The widened sinuses contain enlarged and desquamated endothelial cells. The lymphatic tissue show small germinal centers. Tumor cells are not present.

Diagnosis Left mastectomy specimen with fresh biopsy wound. Diffuse lobular carcinoma in situ in all parts of the breast with atypical intralobular and intraductal proliferation (type "B", rarely type "A") and multifocal development of small cell carcinoma. No evidence of metastasis in major pectoral muscle or axillary lymph nodes.

460 . R. Bassler and H. Kronsbein

Postoperative Course

Radiation was done with telecobalt 60 in 75 sessions and a total dose of 5,000 rad. A scintigram of the liver and skeleton did not reveal any metastases. Clinical control one year after mastectomy showed slight edema of the left forearm but no metastasis. Mammography of the right breast was not remarkable and no lump was palpable.

Disseminated Lobular Carcinoma of the Breast .


Results In the above case report we described a special form of LCIS with multiple areas of invasive cancer and involvement of all lobules of the left breast of a 61-year-old woman. Gross Features

The gross and microscopic findings of the biopsy and of the radical mastectomy specimen reveal a diffuse tumor originating from the acinar and ductular epithelium. This explains the clinical symptom of a diffuse enlargement and induration of the breast before biopsy and the lack of a circumscribed tumor. Therefore the specimen (Fig. I) consists of white and brownish breast tissue surrounded by lobules of fat tissue and without tumor nodules or cysts. Only the slightly brownish color of the tissue in some areas rich of lobules appeared remarkable (Fig. 1, arrows). Number, Size and Shape of the Lobules

In many descriptions of LCIS the number of lobules showing the lesion was between one and ten (or more). In two other cases of our own material serial sections of the mastectomy specimen revealed widespread LCIS with many foci in the area adjacent to and distant from the biopsy wound (Bassler, 1978). In mastectomy specimens Citoler and Zippel (1975) found only four lobules per case of type "A" LCIS and nineteen lobules in type "B" cases. These authors conclude that the "B"-type is the more progressive form of LCIS. Haagensen et al, (1978) noted that "occasionally the lobular neoplasia is truly massive in extent, being seen almost everywhere in the tissues available for study". In our case we have investigated 1,233 lobules in parallel slices and serial sections. 1,225 lobules show a proliferating and atypical cell pattern and only 8 lobules have a normal epithelium. The lobules are frequently enlarged forming lobular macroacini solidly filled with proliferating tumor cells (Fig. 2). Macroacini as described by Haagensen et al. (1978) were observed in only 7,5%, i.e., in 93 of 1,233 lobules (Fig. 3a). The size of the lobules is not only correlated closely with the number of proliferated cells. 2-6 lobules in every slide exhibit an edema of the intralobular connecti ve tissue (so-called Mantelgewebe) with an increased diameter of the entire lobule (Fig. 2, 3 c). In other sections, lobules are not enlarged, but nevertheless occupied by tumor cells which are arranged in small rows averaging 2-3 cells in thickness. We also found a slight edema of the connective tissue (Fig. 3). Rosen et al. (1978) have attempted to estimate

462 . R. Bassler and H. Kronsbein

the variations in LCIS and found in 213 of the cases enlargements of the lobules of two or more.

Lymphoid Reaction Lymphoid Reaction in and immediately around the lobules was generally weak. More than one half of the slides displays either no or only few infiltrates and marked reactions in the surrounding tissue of only two lobules. The distribution of the intensity of lymphoid reactions correlates well with the findings of Rosen et al. (1978).

Involvement of Ducts The sections show a frequent extension of the cell proliferations into the terminal ducts. The cell pattern corresponds to that of the proliferating cells of the lobules. We found involvement of terminal ducts in two thirds of the slides and a confinement of LCIS to the lobules in one third. In six slides and corresponding serial sections we observed an extension into small and medium-sized ducts with histological signs of an intraductal noninvasive carcinoma, here mostly with uniform small cells without mitoses corresponding to type "A". Fechner (1972) confirms these findings, and Rosen et al. (1978) found duct involvement in 64 cases and no involvement in 33 cases. The larger ducts showed mainly a slight ectasia and occasionally linear epithelial proliferations. Cysts with apocrine metaplasia are generally not involved.

Cell Types of LCIS and Invasive Carcinoma The typical and most frequent forms of LCIS are characterized by proliferating uniform solid sheets of cohesive cells. They were classified by Haagensen (1971) as type "A" while the pleomorphic, irregular forms with hyperchromatic nuclei and loss of cohesion were called type "B". In our case we found predominantly "B" and "BI A"-type cells and only very rarely "A"- or "A/B"-type cells in the lobules and terminal ducts in a ratio of about 25 : 5. Groups of "A"-type cells fill up only some lobules but more ductules and small ducts (Fig. 4). Frequently both cell patterns and intermediate forms with small clefts between the cells (Fig. 4 b, c) were seen with increasing pleomorphism, loss of cohesion (Fig. 5) and increase in the size of the proliferating cells with enlargement of the nuclei. Mitoses are infrequent in both cell types. The cytoplasm stains pink and the PAS-stain revealed granular or vacuolar deposits of acid mucopolysaccharides around the nuclei. We found mainly granular and infrequently

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Fig. 3. Enlarged lobule with intensive proliferation of atypical epithelial small cells with large hyperchromatic nuclei (a). High magnification (b) with preserved small lumina. (c) LCIS involving the ductules (B-type cells) in a small fibroadenoma. HE, X 120 (a) and X 240 (b, c).

4 64 . R. Bassler and H. Kronsbcin

vacuolar mucopolysaccharides in 70-80% of the "B"-type cells and in 10-20% of "A"-type cells. In a few lobules and in the basal cell row of ductules we observed the development of polygonal cells with clear cytoplasm and enlarged nuclei. The so-called pagetoid cells are derived from basal cells and were frequently seen in intralobular ductules (Fig. 8). Sometimes we found a closely packed cell mass in the lobules in contrast to a more regular pattern in other areas. The Basal Membrane surrounds the lobules and ducts with extension into the intralobular tissue. The membrane is PAS-positive. A reticulum stain revealed an intact membrane in the LCIS areas with protrusions but without clefts (Andersen, 1975, 1977). Defects occur only in areas with tumor invasion (Fig. 7).

Invasive Lobular Carcinoma

In 690 slides of our case we found fifteen areas with an infiltrating mainly small cell carcinoma with an Indian file pattern. The cells invade the surrounding connective and fat tissue diffusely. The growth pattern of this small cell carcinoma is mostly uniform. The invasive areas are generally small and therefore it seems possible to determine the lobule or groups of lobules from which the invasive growth has originated. An early phase of the infiltrating tumor is illustrated in Fig. 6 showing a complete loss of cohesion and a high grade of atypia of the tumor cells. Single cells migrate into the surrounding connective tissue splitting up the basal membrane (Fig. 7) of lobules or ductules, Two areas exhibit the pattern of an invasive ductal carcinoma showing solid cords and an adenoid pattern with marked stromal fibrosis. Another slide displays foci with a tubular and lobular invasive carcinoma which is interpreted as a tubular variant of lobular invasive carcinoma by Fisher et al. (1977). The classic histologic appearance of LCIS and its invasive phase is characterized by proliferation of uniform pleomorphic cells within the lobules or infiltrating into the stroma. The tumor is usually confined to one area of the breast and does not invade the whole organ. Especially LeIS is limited to some lobules or groups of lobules and their ductules with an average of 4-19 lobules being involved (Citoler and Zippel, 1975; Haagensen et al., 1978). Of importance in the described case is the fact that all lobules of the entire breast are affected by proliferation of various epithelial cells occupying the lobules and the lobulo-ductular segments. In comparison to the usual lobular carcinoma of the breast this case appears quite unique considering the wide distribution and particular cell pattern. Therefore we call this tumor a disseminate form of lobular carcinoma. The

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Fig. 4. Lobule's with distended acini filled with uniform cells of the A-type (a). High magnification shows some irregular cells with small intercellular clefts (b) and loss of cell cohesion (c). HE, X 150 (a) and X 240 (b, c).

epithelial proliferations in more than 1,000 investigated lobules revealed different phases in the development of the tumor. Thus new questions arise as to the histogenesis and cytology of this lesion. The ratio of lobules with cells of the "A"- or "A/B"-type to the "B"or "BI A"-type ist 5 : 25 showing occasional areas with uniform cell proliferations of the "A"-type with a tendency to extend into the adjacent ductules (Fechner, 1972) (Fig. 4 a). In some macroacini cell groups of the

Fig. 5. LeIS with pleomorphic cells and hyperchromatic nuclei (B-type), note irregular loss of cell-cohesion. HE, X 240.

Disseminated Lobular Carcinoma of the Breast


Fig. 7. LCIS with progression to invasive small-cell carcinoma. Cells migrate into the connective tissue by splitting up the basal membrane (arrows). Reticulum stain (Gomori), X


two types were close together without a sharp borderline. Some of the foci of LeIS belonging to the "A"-type were moderately irregular and showed small clefts between the tumor cells and more mucin deposits than usual (Fig. 4 b). We interpret these changes as the early steps of transition to the pleomorphic "B" -type with an increased loss of cell cohesion (Fig. 4 b) and with augmentation of atypical cells with hyperchromatic nuclei (Fig. s, 6). The cytoplasm of the "B" -cells contain much more mucin in specimens of the in situ and invasive tumor phase (Gad and Azzopardi, 1975). Recently Steinbrecher and Silverberg (I975) reported five cases of a mucinous variant of lobular carcinoma with signet-ring cells. In our case the "B"-type cells predominate and they fill up even the acini of small lobules and the narrow clefts of fibroadenomas (Fig. 3 c).

468 . R. Bassler and H. Kronsbein

Fig. 8. Early phases of development of LeIS in a ductule (a) and in transversely cut lobules (b) with proliferation of pager-like cells in the basal row of the glandular epithelium. This is elevated by the tumor-cells; some lobules are occupied by cells of the pleomorphic B-type. HE, X 320.

The tumor cells have pleomorphic hyperchromatic nuclei and exhibit a focal loss of cohesion indicating primary "B" -type cells (Fig. 3). This type also predominates in the areas of invasive cancer (Fig. 8) and is, in our opinion, of importance in the prognostic assessment of this tumor. The tumor cells arise from the basal row of the lobular or ductular epithelium, i.e., the basal cells, whereas the myoepithelial cells do not proliferate in the in situ phase and are well preserved. The basal cells are the matrix of both types of lobular carcinoma, the pagetoid cells being variants of the basal cells. In our case we observed pagetoid cells only in the early phase of proliferation with elevation of the superficial cell rows (Fig. 8). In lobules with carcinoma in situ pagetoid cells are usually found in small numbers or are completely absent. Therefore we suppose that the pagetoid cells are intermediate forms of basal cells and their appearance depends on the intensity and quantity of cell proliferation.

Disseminated Lobul ar Carcinoma of th e Breast . 469

The exceptional distribution of the lobular carcinoma including all investigated lobules and the different stages in the development of the LCIS with transition to the invasive phase are the essential features of this unusual case. LCIS is frequently multicentric and bilateral in about 25-3°% of the cases (Newman, 1963; Me Di vitt et a1., 1967 ; Hutter and Foote , 1969, 1970 ; Ashikari, 1973; Andersen, 1974, 1977; Bassler, 1969, 197 8). The above described case is, to a certain degree, an ad vanced form of primary multicentric cancer or, in other words , a "holoblastic carcinoma" originating from the basal cells of all lobules and lobulo-ductular segments of the brea st caused by a carcinogenic stimulus acting on the entire breast epithelium. A cknowledgment. The authors are grateful to Prof. E. Goltner, H ead of the Dept. of Gynec ology, City and Academi c Hospital Fulda, who kindly provided the clinical data.

References Andersen, J. A.: Lobul ar ca rcinoma in situ. Acta path. microbiol, sca nd. A 82, 5'9-533 ( 1974) Andersen, ]. A.: The basement membran e and lobular carcinoma in sit u of the brea st. Acta path . microbiol, scand. A 8), 245- 250 (1975) Andersen, J. A.: Lobular carcinoma in situ of the bre ast. Can cer )9, 2597-2602 (1977) Ashikari, R., Huvos, A. G., Urban, J. A., and Robb ins, G. F. : In filtrat ing lobular carcinoma of the breast . Can cer JI , I 10-116 (1973) Bassler, R .: Das sogenannte lobular e Karzinom der Ma mma. Pathologic und klinische Kon sequ enzen . Dtsch. med. Wschr. 94,108-113 (1969) Bassler, R. : Pathologic der Brusrdriise. In: Spez. pathologische An at ornie, hrsg, von W. Do err, G. Seifert und E. Uehlin ger, Band I I . Springer-Verlag, Berlin-HeidelbergN ew York (1978) Breslow, A., and Bran caccio, M. E.: Int racellular mucin pr odu ctio n by lobular bre ast carcinom cells. Ar ch. P ath. Lab. Med. 100 , 620-621 (1076) Citoler, P. und Zippel, H. H. : D as Ca rcinoma in situ der Mamm a. Verh . drsch, Ges. P ath . 59, 549 (1975) C itoler, P. und Zippel, H . H . : Mo rphologische Beobachtungen zu r Differenzierung von Vor- und Friihstadien des Mam makarzinoms. Arch. Gynak, 224, 5'8 (1977) Fechner, R. E.: Epithelial alte ra tions in th e extralobular ducts of br easts with lobular carcinoma. Arch. Path. 9) , 164-1 71 (1972) Fisher, E. R., Gre gorio, R. M., Redmon d, c., and Fisher. B.: T ubulolob ula r invasive brea st can cer ; variant of lobul ar in vasive carcinoma . Hum. Path. 8, 679- 683 (1977) Foote, F. W., and St ewart, F. W. : Lobular carcinoma in situ - A rare fo rm of mammary cancer. Amer, ]. Path. 1] ,491-495 (1941) Gad , A., and Az zop ardi, ]. G.: Lobular car cinom a of the breas t: A special variant of mucin secreting carcinoma . ]. clin, Path. 28,7 11- 716 (1975) H aagen sen, C. D. : Diseases of the Breast. Second Edi ti on. W. B. Saunders, PhiladelphiaLond on- T oronto (1971) 31 Path. Res. Pract. Vol. 166

470 . R. Bassler and H. Kronsbein Haagensen, C. D., Lane, N., Lattes, R., and Bodian, C.: Lobular neoplasia (so-called lobular carcinoma in situ) of the Breast. Cancer 42,737-769 (1978) Hutter, R. V. P., and Foote, F. W. R.: Lobular carcinoma in situ. Long term follow up. Cancer 24,1081-1085 (1969) Hutter, R. V. P., Foote, F. W., and Farrow, J. H.: In situ lobular carcinoma of the female breast. 1939-1968. In: Breast cancer early and late, p. 201. Year Book Medical Publ, Inc., Chicago/Ill. (1970) McDivitt, 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 risk. J. Amer. med. Ass. 201, 82-86 (1967) Newman, W.: In situ lobular carcinoma of the breast. Report of 26 women with 32 cancers. Ann. Surg. 157, 591-599 (1963) Rosen, P. P., Lieberman, P. H., Braun, D. W., Kosloff, C., and Adair, F.: Lobular carcinoma in situ of the breast. Detailed analysis of 99 patients with average follow up of 24 years. Amer. J. Surg. Path. 2, 225-251 (1978) Steinbrecher, J. S., and Silverberg, S. G.: Signet-ring cell carcinoma of the breast. The mucinous variant of infiltrating lobular carcinoma? Cancer 37, 828-840 (1976) Received February 16, 1979 . Accepted March 12, 1979

Key words: Breast cancer - Lobular carcinoma tn situ - Invasive lobular carcinoma - Disseminated lobular carcinoma Prof. Dr. R. Bassler, Parhologisches Institut der Stadt. Kliniken, Pacelliallee 4, D-6400 Fulda, West Germany