ANATOMIC PATHOLOGY Original Article

C a n c e r i z a t i o n o f S m a l l E c t a t i c D u c t s o f t h e B r e a s t b y D u c t a l

C a r c i n o m a I n S i t u C e l l s W i t h A p o c r i n e S n o u t s

A Lesion Associated With Tubular Carcinoma

NEAL S. GOLDSTEIN, MD, AND BARBARA A. O'MALLEY, MD

Small ectatic ducts lined by atypical ductal cells with apocrine snouts occasionally have been observed in association with tubu­lar carcinoma; some pathologists have considered these carcinomas to be a form of ductal carcinoma in situ (DCIS). Thirty-two cases of tubular carcinoma, 41 of invasive grade 1 ductal carcinoma with DCIS, 40 of invasive grade 1 ductal carcinoma without DCIS, 40 of invasive grade 3 ductal carcinoma, 40 of invasive lobular carci­noma, 20 of well-differentiated DCIS, and 80 of fibrocystic changes were examined to determine the relationship between the lesion formed by atypical ductal cells with apocrine snouts and invasive carcinoma, DCIS, and benign breast changes. Seventeen cases con­tained lesions formed by atypical ductal cells with apocrine snouts: 14 were associated with tubular carcinoma (43.7%), and 3 with invasive grade 1 ductal carcinoma (3.7%). In six invasive carci­nomas, the associated DCIS was formed by cells identical to those within the lesion. These lesions were found at the periphery of the

Columnar changes of the epithelium in small ectatic ducts of the breast are common and usually recogniz­able as benign. Weidner,1 in a recent review article on malignant breast lesions that mimic benign tumors, was the first to describe a lesion composed of small ectatic ducts that were lined by one or two layers of atypical cells with apocrine snouts. This lesion was considered well-differentiated intraductal carcinoma and was associated with tubular carcinoma. The cells that comprised this lesion differed from those in typi­cal, benign, columnar change within small ectatic ducts and were morphologically identical to the cells that formed the tubules of the invasive carcinoma.

From the Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan.

Manuscript received August 13, 1996; revision accepted September 25,1996.

Address reprint requests to Dr Goldstein: Department of Anatomic Pathology, William Beaumont Hospital, 3601 West 13 Mile Rd, Royal Oak, Ml 48073.

invasive carcinoma and adjacent to the DCIS. The lesions were probably composed of low-grade intraductal malignant epithelial cells, which partially involve small ectatic ducts and are often adja­cent structures as a form of cancerization. This cytologic and archi­tectural form of DCIS appears to be related to an invasive carci­noma that is usually of tubular subtype. Attention to this form of cancerization by malignant intraductal cells, especially with regard to specimen surgical margins, is imperative when a tubular carci­noma is encountered. If a pathologist encounters only this lesion in a partially sampled breast biopsy specimen, additional (or all) tissue should be submitted for histologic evaluation to ensure that an invasive carcinoma is not missed. This lesion needs to be distin­guished from the frequent, benign, columnar alteration within lob­ules and small ectatic ducts. (Key words: Breast; Intraductal carci­noma; Atypical ductal hyperplasia; Adenosis) Am J Clin Pathol 1997;107:561-566.

We occasionally have encountered such lesions and have noted that they frequently engender colle-gial discussion about their classification and biologic significance. We reviewed the l i terature review regarding tubular carcinoma, and found no mention of atypical ductal cells with apocrine snouts involv­ing small ectatic ducts. To our knowledge, this lesion has not been systematically studied.2-14 One study did note that intraductal carcinoma associated with tubular carcinoma was focally composed of these cells.15 We retrospectively reviewed cases of invasive carcinoma, in situ carcinoma, and fibrocystic change to characterize the lesions formed by atypical ductal cells with apocrine snouts and study their relation­ship with different benign and malignant lesions.

MATERIALS AND METHODS

We used the departmental computer information system to search the anatomic pathology file at William Beaumont Hospital (Royal Oak, Mich) for all cases of invasive breast carcinoma from 1991 to 1993.

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562 ANATOMIC PATHOLOGY Original

Of the 771 invasive carcinomas identified, 617 (80%) were invasive ductal carcinomas, 95 (12.3%) were invasive lobular carcinomas, 32 (4.1%) were tubular carcinomas, and the remainder were other subtypes. These 771 cases comprised the database from which the first five study groups were derived. The first study group included the 32 tubular carcinomas. The second study group included the first 41 consecutive small (greatest diameter, < 2 cm), grade 1 invasive ductal carcinomas with an associated ductal carci­noma in situ (DCIS). The third group included the first 40 consecutive small, grade 1 invasive ductal car­cinomas wi thout an associated DCIS. The fourth group was composed of the first 40 consecutive small, grade 3 invasive ductal carcinomas with an associated DCIS. The fifth group included the first 40 consecu­tive invasive lobular carcinomas; 80% of these carci­nomas were pathologic stage T2 or T3 (mean maximal diameter, 4.6 cm). The first 20 consecutive cases of pure, well-differentiated DCIS accessioned during 1993 constituted the sixth group. The first 40 consecu­tive cases of fibrocystic change without epithelial hyperplasia accessioned during 1993 constituted the seventh g roup . Finally, the e ighth s tudy g roup included the first 40 consecutive cases of fibrocystic change with epithelial hyperplasia without atypia accessioned during 1993.

All slides from the patients' breast-related proce­dures, including biopsies, lumpectomies, and mastec­tomies, were examined. Well-differentiated DCIS had nuclei that were usually small with little variation in size. They had smooth nuclear membranes, uniform chromatin, and occasional punctate nucleoli. The cells were monomorphic and evenly spaced. The invasive carcinomas were categorized by the criteria of Page and Anderson.16 Tubular carcinomas had a haphazard proliferation of slightly dilated tubules with pointed, angu la r ends (Fig 1). Some lumina con ta ined eosinophilic secretions. These tubules were lined by a single layer of regular columnar epithelial cells that had cytologically low-grade nuclei and moderate amounts of eosinophilic cytoplasm that formed apoc­rine snouts.2-6-8'10 We used the criteria of Elston and Ellis17 to classify the invasive ductal carcinomas as g rade 1 or 3 and the cr i ter ia of Page and col­leagues16,18 to distinguish intraductal carcinoma from atypical ductal hyperplasia.

We recorded the presence or absence of atypical ductal cells with apocrine snouts within each lesion and their location in relation to the invasive carci­noma or DCIS. The structures involved by these cells were categorized as small acini, ectatic small ducts,

medium ducts, or large ducts. The histologic features of these cells are described below.

The predominant architectural pattern of the DCIS was categorized as clinging, solid, cribriform, cen­trally necrotic, or micropapillary. The predominant and highest grade of DCIS associated with the tubular carcinomas was recorded.

RESULTS ,

The atypical ductal cells with apocrine snouts usu­ally formed a single cell layer around small ectatic ducts; however, occasional ducts were lined by two cell layers (Figs 1-3). The cells did not form micropap­illary or cribriform structures within the small ectatic duc t s . All cells had a m o d e r a t e a m o u n t of eosinophil ic cytoplasm and prominen t apocrine snouts. In contrast to typical ductal cells, the atypical ductal cells with apocrine snouts were larger (Figs 3 and 4). They contained sparser and more coarsely configured chromatin with one or two punctate nucle­oli and had thicker, more irregular nuclear contours. Mitoses were rare or absent. The atypical ductal cells with apocrine snouts were morphologically indistin­guishable from the cells that comprised the associated invasive carcinoma (Fig 5). 4

Seventeen cases contained lesions formed by atypi­cal ductal cells with apocrine snouts (Table); all 17 were associated with an invasive carcinoma. Fourteen ' of these cases were associated with tubular carcinoma, and three with invasive grade 1 ductal carcinoma (two had an associated DCIS). None were associated with * cases of pure well-differentiated DCIS, invasive grade 3 ductal carcinoma, invasive lobular carcinoma, fibro­cystic change with epithelial hyperplasia, or fibrocys- ' tic change without epithelial hyperplasia.

The DCIS associated with the lesion was formed by atypical ductal cells with apocrine snouts, identi­cal to those that lined the small ectatic ducts in six invasive carcinomas (five tubular and one grade 1 ductal). All six cases had a cribriform and micropap­illary architecture. The structures that were involved by atypical ductal cells with apocrine snouts were at the periphery of the invasive carcinoma and adja- «• cent to the DCIS. All lesions were within 1 cm of the advancing edge of the invasive carcinoma. Four cases had a single layer of atypical ductal cells with \ apocrine snouts in medium ducts in addition to the involved small ectatic ducts. In one case, these cells were in the small acini of a lobule that was contigu- > ous with small ectatic ducts, which were also lined by these cells.

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GOLDSTEIN AND O'MALLEY 563

•rn of Small Ectatic Ducts Cancerization

FIG 1. Tubular carcinoma with a small ectatic duct lined by atypical ductal cells with apocrine snouts located in the upper portion of the figure (hematoxylin-eosin, 60x).

FIG 3. High power of two small ectatic ducts lined by atypical ductal cells with apocrine snouts. Compare these cells with those of typical columnar change of small ectatic ducts and tubular car­cinoma in Figures 4 and 5 (hematoxylin-eosin, 384x).

Fourteen (43.7%) of 32 cases of tubular carcinomas had the lesion formed by atypical ductal cells with apocrine snouts (Table). All lesions were present in a tubular carcinoma that had an associated DCIS. None of the eight cases of tubular carcinomas that were devoid of DCIS had the lesion. In the 14 cases of tubu­lar carcinoma that had the lesion, the DCIS was well differentiated. Ten cases had a mixture of cribriform, micropapillary, and clinging architectural patterns, and four were purely cribriform pattern.

Three (3.7%) of 81 cases of invasive well-differenti­ated ductal carcinoma had small ectatic ducts lined by atypical ductal cells with apocrine snouts. Two cases

FIG 2. Medium power of the small ectatic ducts lined by atypical ductal cells with apocrine snouts from Figure 1. Note the cytologic similarity of the cells with the cells of two tubular carcinoma ducts located below the ducts (hematoxylin-eosin, 192x).

FIG 4. Typical columnar change of the cells that line small ectatic ducts. These cells are smaller and uniform and have bland chromatin compared with atypical ductal cells with apocrine snouts (hematoxylin-eosin, 540x).

had pure cribriform, grade 1 DCIS. One invasive grade 1 ductal carcinoma had the lesion but no DCIS. Although the invasive ductal carcinomas were pure ductal type without a tubular component, some cells that comprised the invasive ductal carcinoma also had apocrine snouts.

DISCUSSION

The lesion formed by small ectatic ducts lined by atypical ductal cells with apocrine snouts was present in 14 (43.7%) of 32 cases of tubular carcinoma. In contrast, these lesions were found in only 3 (3.7%) of 81 cases of

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564 ANATOMIC PATHOLOGY Original Article

invasive grade 1 ductal carcinoma and in no cases of invasive grade 3 ductal invasive carcinoma, pure well-differentiated DCIS, or fibrocystic change. The atypical ductal cells with apocrine snouts were morphologically identical to cells that comprised the invasive carci­noma.15 Sixteen (94%) of 17 lesions were associated with an invasive carcinoma with DCIS. Six cases also had cribriform and micropapillary DCIS that was formed by atypical ductal cells with apocrine snouts.

These results suggest that small ectatic ducts lined by atypical ductal cells with apocrine snouts are related to tubular carcinoma or the associated DCIS. We believe that atypical ductal cells with apocrine snouts are well-differentiated malignant epithelial cells because of their location adjacent to invasive car­cinoma and DCIS and because of their morphologic

->it'-

FIG 5. Typical tubular carcinoma composed of atypical cells with apocrine snouts. The cells that comprise the invasive carcinoma are similar to the atypical ductal cells with apocrine snouts within small ectatic ducts (hematoxylin-eosin, 222x).

similarity with the cells that comprise the associated invasive carcinoma. Fechner19 called attention to the fact that malignant ductal carcinoma can partially involve breast lobules; Azzopardi and others popular­ized this observation as "cancerization of lobules."20,21

Since then, partial or complete replacement of benign epithelial cells by atypical or malignant epithelial cells has been described in a variety of lesions, all of which are variants on the theme of cancerization of lobules by DCIS.22-33 Atypical ductal hyperplasia also can be a pattern of lobular cancerization, as it has been found around the periphery of DCIS.34 We believe that the pattern of involvement of slightly dilated ducts by the atypical ductal cells with apocrine snouts is also a form of lobular cancerization, albeit by well-differen­tiated malignant cells that partially involve small ectatic ducts in a single or double cell layer.

Whether this lesion is considered a distinctive pat­tern of DCIS or lobular cancerization by malignant intraductal carcinoma cells is predominantly a termi­nology issue. Holland et al35 demonstrated the lesion in Figure 8 of their recent DCIS grading and classifica­tion treatise and considered it well-differentiated clinging DCIS. Weidner1 also considered it a form of DCIS. The main practical issue is that pathologists must recognize the malignant nature of this lesion, especially in determining the need for additional sur­gical excisions. Given the peripheral location of the lesion to invasive carcinoma, it would not be unex­pected for a surgical excision margin to transect it. Most studies have shown the need to procure nega­tive margins of resection (either DCIS or invasive car­cinoma) in breast-conserving surgery.36-38 Regardless of the term used, pathologists must identify this lesion as a form of intraductal malignancy and note its relationship to the surgical margin.

DISTRIBUTION OF BREAST LESIONS ASSOCIATED WITH SMALL ECTATIC DUCTS LINED BY ATYPICAL DUCTAL CELLS WITH APOCRINE SNOUTS

Breast Lesion No. of Cases Examined No. of Cases With Lesion

Tubular carcinoma without DCIS Tubular carcinoma with DCIS Invasive grade 1 ductal carcinoma with DCIS Invasive grade 1 ductal carcinoma without DCIS Invasive grade 3 ductal carcinoma with DCIS Invasive lobular carcinoma Pure nuclear grade 1 intraductal carcinoma Fibrocystic changes with epithelial hyperplasia Fibrocystic changes without epithelial hyperplasia

24 41 40 40 40 16 40 40

0 14 2 1 0 0 0 0 0

DCIS = ductal carcinoma in situ.

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GOLDSTEIN AND O'MALLEY 565 Cancerization Pattern of Small Ectatic Ducts

In particular, this lesion must be distinguished from simple columnar transformation of small ectatic ducts, also termed "blunt duct adenosis."2 7 , 3 9 - 4 1 At low-power magnification, these two lesions appear similar: small, slightly ectatic ducts lined by a single cell layer. However, there is a clear-cut distinction at higher mag­nifications. In contrast to the cells in the lesion we describe, the cells of columnar alteration of small ectatic ducts line up in a uniform manner, are smaller and more columnar, and have more evenly distrib­uted, slightly hyperchromatic chromatin. This benign alteration of small ectatic ducts and lobules has no proved or suggested premalignant significance.16

Another entity that may be confused with the lesion we descr ibe is apocr ine metap las ia that involves small ectatic ducts.27,42,43 At higher magni­fication, the cells of both lesions have prominent apocrine snouts. The cells of apocrine metaplasia, however, are larger and more cuboidal. They also have coarser cytoplasmic apocrine granules, a central round nucleus, and a more prominent nucleolus.

A second practical aspect of cancerization or DCIS of small ectatic ducts with apocrine snouts is its asso­ciation with invasive carcinoma, which is most com­monly of tubular type. If a pathologist encounters this lesion in a partially sampled breast biopsy specimen, additional, preferably all, tissue should be submitted for histologic evaluation to ensure that an invasive carcinoma is not missed.

In summary, we have described 17 breast lesions composed of small ectatic ducts lined by atypical duc­tal cells with apocrine snouts. These cells were identi­cal to those of the associated invasive carcinoma, which was almost always of tubular type. This lesion can be considered either DCIS or cancerization of small ectatic ducts by well-differentiated intraductal carcinoma cells. Pathologists should be cognizant of this microscopic lesion and its association with inva­sive carcinoma so as not to misinterpret it as typical columnar change of small ectatic ducts.

Acknowledgments: We thank Drs J Neill, J Watts, and R Goldstein for their manuscript reviews.

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