Papillary lesions of the breast: selected diagnostic and management issues

Transcription

1 Histopathology 2008, 52, DOI: /j x REVIEW Papillary lesions of the breast: selected diagnostic and management issues L C Collins & S J Schnitt Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA Collins L C & Schnitt S J (2008) Histopathology 52, Papillary lesions of the breast: selected diagnostic and management issues The assessment and categorization of papillary lesions remains one of the most challenging areas in breast pathology. In this review, we will focus on several diagnostic and management issues related to papillary breast lesions that are frequently encountered in daily practice. These include: (i) the distinctions among papillomas with atypia (atypical papillomas), papillomas with ductal carcinoma in situ, and papillary ductal carcinoma in situ; (ii) recent developments in our understanding of encapsulated ( intracystic ) papillary carcinomas and solid papillary carcinomas; and (iii) the impact of core needle biopsy on management decisions and specimen evaluation. The role of immunohistochemistry in the evaluation of these lesions, particularly the role of myoepithelial cell markers, will be emphasized. Keywords: breast, carcinoma, ductal carcinoma in situ, papillary, papilloma Abbreviations: ADH, atypical ductal hyperplasia; CK, cytokeratin; DCIS, ductal carcinoma in situ; H&E, haematoxylin and eosin; SMMHC, smooth muscle myosin heavy chain; UDH, usual ductal hyperplasia Introduction Address for correspondence: L C Collins, Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. lcollins@bidmc.harvard.edu Surgical pathologists generally have little difficulty in identifying a breast lesion as papillary based upon finding a proliferation characterized by finger-like projections or fronds composed of central fibrovascular cores covered by epithelium. However, once identified as papillary, the categorization of the lesion as benign, atypical or malignant is often problematic, even for experienced pathologists. Furthermore, even when recognized as a carcinoma, it may be difficult to determine if a papillary lesion is in situ, invasive, or a combination of the two. A detailed review of papillary breast lesions has recently been published by Mulligan and O Malley. 1 The purpose of this review, therefore, is to focus on several selected problems in the evaluation of papillary lesions that we repeatedly encounter in our clinical and consultation practice. These include: (i) the identification of atypia in a papilloma and the distinctions among papillomas with atypia (atypical papillomas), papillomas with ductal carcinoma in situ, and papillary ductal carcinoma in situ; (ii) recent developments in our understanding of encapsulated ( intracystic ) papillary carcinomas and solid papillary carcinomas; and (iii) the management of patients with papillary lesions diagnosed on core needle biopsy and the problem of displaced epithelium following needle biopsy. In addition, the role of immunohistochemistry in the evaluation of these lesions will be emphasized where appropriate. Papilloma with atypia (atypical papilloma), papilloma with ductal carcinoma in situ, and papillary ductal carcinoma in situ papilloma with atypia (atypical papilloma) and papilloma with ductal carcinoma in situ The papillary fronds of benign intraductal papillomas are covered by an inner myoepithelial cell layer and an Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Publishing Limited.

2 Papillary breast lesions 21 A B Figure 2. Intraductal papilloma. Immunohistochemistry for smooth muscle myosin heavy chain demonstrates myoepithelial cells within papillae and surrounding the involved duct. Figure 1. Intraductal papilloma. A, Low-power view illustrating papillae with variably fibrotic cores. B, Higher-power view demonstrates characteristic outer epithelial and inner myoepithelial cell layers. outer epithelial layer. In addition, myoepithelial cells surround the involved duct. The epithelial layer may consist of one or a few layers of cuboidal to columnar cells, or may show varying degrees of usual ductal hyperplasia (Figures 1 and 2). The hyperplasia may be extreme and may grow in a contiguous fashion between adjacent papillae. Some intraductal papillomas exhibit areas of epithelial proliferation that fulfil the combined architectural and cytological criteria for the diagnosis of atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS). These areas may involve the papilloma to a varying extent, but features of a benign papilloma remain evident in part of the lesion (Figures 3 and 4). When DCIS is present, it is most often of low or intermediate nuclear grade, with solid, cribriform and or micropapillary patterns. Small foci of necrosis may be observed. Of note, myoepithelial cells are reduced or absent in the foci of ADH or DCIS, but Figure 3. Atypical papilloma. Most of this lesion consists of an intraductal papilloma without atypia. In a few areas, the epithelial cells are monomorphic and show polarization around sharply defined lumina, similar to the pattern seen in atypical ductal hyperplasia (arrows). remain readily identifiable in areas of residual benign papilloma and around the periphery of the involved spaces (Figure 4C). In addition, the epithelial cells comprising atypical foci lack expression of high-molecular-weight cytokeratins (CK; such as CK5 6) and typically show expression of oestrogen receptors. 1 In fact, in problematic cases, the absence of high-molecular-weight CK immunoreactivity is a useful adjunct to help distinguish between ADH or DCIS and usual ductal hyperplasia (UDH) in a papilloma. There are no universally accepted criteria for distinguishing atypical papilloma and papilloma with DCIS from each other. Moreover, some authorities include in

3 22 L C Collins & S J Schnitt A B C Figure 4. Papilloma with ductal carcinoma in situ (DCIS). A, An area of residual benign intraductal papilloma is apparent on the left side of this image. However, much of this lesion shows monotonous epithelial proliferation in a solid and cribriform pattern, indicative of DCIS. B, Higher-power view of DCIS within the papilloma. C, p63 immunohistochemistry shows that myoepithelial cells are present within the papillae of the residual papilloma (left) and are greatly reduced in number in the portion of the papilloma occupied by DCIS (right). the definition of papilloma with ADH or atypical papilloma not only papillomas that contain areas of ADH, but also those that exhibit areas diagnostic of non-high-grade DCIS that are limited in size or extent. For example, Page et al. categorize a lesion as papilloma with DCIS when the papilloma shows any area of uniform histology and cytology consistent with noncomedo DCIS that is >3 mm in size. In contrast, papillomas that contain a histologically identical epithelial proliferation that is 3 mm in size are classified as papillomas with atypia. 2 Tavassoli classifies a lesion as carcinoma arising in a papilloma when the atypical population of cells involves at least a third but <90% of the lesion. In contrast, she classifies a lesion as an atypical papilloma if less than one-third of a lesion shows these same changes. 3 Others render a diagnosis of papilloma with DCIS if the atypical proliferation in the papilloma shows all of the combined architectural and cytological features of DCIS regardless of its extent, 4 an approach to which we subscribe. The clinical significance of atypia or DCIS in a papilloma is not well-defined. Page et al. have reported a substantially increased risk (7.5-fold) for the subsequent development of breast cancer, predominantly in the ipsilateral breast, in patients with lesions they categorized as papillomas with atypia using the definition noted above. 2 However, there were only eight patients with atypical papillomas in that study. In contrast, using a similar definition for atypical papilloma but in a larger study population, Lewis et al. have found that the level of breast cancer risk associated with papillomas with atypia is similar to that of patients with ADH elsewhere in the breast (4 5-fold) and that the risk is approximately equal in both breasts. These authors have also noted that the breast cancer risk is particularly high (sevenfold) among women with multiple papillomas with atypia. 5 It could be argued that distinguishing between atypical papilloma and papilloma with DCIS is of questionable clinical importance. Available outcome

4 Papillary breast lesions 23 data suggest that the risk of recurrence does not appear to be related to the extent of atypia or DCIS within the papilloma. 6 In fact, the most important consideration in such cases is the presence of atypia or DCIS in the surrounding breast tissue, since this seems to be more closely related to the risk of recurrence than the qualitative features or extent of atypia within the papilloma itself. 2,6 Given the foregoing information, papillomas with atypia and papillomas with DCIS are best managed by complete excision with careful follow-up. The surrounding breast tissue should be carefully evaluated for the presence of ADH and DCIS, as this should be the major feature influencing management decisions. papillary ductal carcinoma in situ Some DCIS have a papillary growth pattern, characterized by fibrovascular cores covered by neoplastic epithelium. In our view, these lesions are fundamentally distinct from papillomas with DCIS. In papillary DCIS, the papillary proliferation is itself neoplastic and there is no evidence of a pre-existing benign papilloma, whereas in papillomas with DCIS, foci of DCIS are engrafted upon the scaffolding of a pre-existing benign papilloma. In such cases, even when the DCIS extensively involves the papilloma, the underlying framework of the papilloma is identifiable, although immunohistochemistry for myoepithelial cells may be required to demonstrate this. Features useful in distinguishing papillary DCIS from benign intraductal papillomas were elucidated more than 40 years ago by Kraus and Neubecker 7 and are summarized in Table 1. In particular, in papillary DCIS, the papillae are usually more delicate and less fibrotic than those of intraductal papilloma. This generally results in a basophilic (blue) appearance of the papillae of papillary DCIS and an eosinophilic (pink) appearance of the papillae of intraductal papillomas on low magnification (Figure 5). Furthermore, the epithelium in papillary DCIS is usually composed of a single cell population with a uniform appearance. The epithelium may consist of one to several layers of columnar cells with varying degrees of stratification (Figure 6), or may show more pronounced proliferation of uniform cells in solid, cribriform or micropapillary growth patterns. Contiguous growth of the epithelium may partially or completely obliterate the spaces between papillae, obscuring the underlying papillary architecture. The nuclei of the neoplastic epithelial cells are most often of low or intermediate grade. Some authors have described and illustrated the presence of myoepithelial cells within the papillae of papillary DCIS, albeit in reduced numbers when compared with intraductal papillomas In our view, lesions illustrated as papillary DCIS that have myoepithelial cells in the papillae probably represent pre-existing benign intraductal papillomas that have become extensively involved by DCIS rather than de novo papillary DCIS. However, a layer of myoepithelial cells is present at the periphery of the involved spaces, a feature that defines this as an in situ process (Figure 7). It should be noted that although most papillary DCIS have a single, uniform cell population, others feature a dimorphic cell population, in which the second population consists of cells with abundant, pale cytoplasm that are most often in a basal location (Figure 8). These Table 1. Histological features useful for distinguishing between intraductal papilloma and papillary ductal carcinoma in situ (DCIS; adapted from Kraus and Neubecker 7 ) Intraductal papilloma Papillary DCIS Cell types Epithelial and myoepithelial Epithelial only Cell orientation Haphazard Uniform, perpendicular to fibrovascular stalks; solid, cribriform or micropapillary patterns may be present Nuclei Normochromatic Hyperchromatic Stroma of papillae Prominent; fibrosis with epithelial entrapment; papillae pink at low magnification Delicate; papillae blue at low magnification Apocrine metaplasia Present Absent Proliferation in adjacent ducts Hyperplasia DCIS

5 24 L C Collins & S J Schnitt A B Figure 7. Papillary ductal carcinoma in situ. This smooth muscle myosin heavy chain immunohistochemistry illustrates that myoepithelial cells are not present within the papillae. However, a myoepithelial layer is present at the periphery of the involved duct. Figure 5. Papillary ductal carcinoma in situ (DCIS; A) and intraductal papilloma (B) photographed at the same magnification. These images illustrate the blue appearance of papillary DCIS in contrast to the pink appearance of intraductal papilloma. Figure 8. Papillary ductal carcinoma in situ with dimorphic cell population. In addition to the neoplastic columnar epithelial cells covering the papillae, a second population of cells with pale cytoplasm is evident, primarily in a basal location. These cells ( globoid cells) should not be mistaken for myoepithelial cells. cells ( globoid cells ) should not be mistaken for myoepithelial cells and can be distinguished from them with immunohistochemical markers for epithelial cells (such as low-molecular-weight CKs) and myoepithelial cells, if necessary. Figure 6. Papillary ductal carcinoma in situ. The papillae are covered by a stratified population of columnar epithelial cells with an increased nuclear cytoplasmic ratio. No myoepithelial cells are present. Encapsulated ( intracystic ) papillary carcinoma Traditionally considered to be a variant of DCIS and termed intracystic or encysted papillary carcinoma,

6 Papillary breast lesions 25 the lesion now called encapsulated papillary carcinoma is characterized by the presence of papillary carcinoma within an apparent cystically dilated duct. These lesions usually present as a subareolar mass and or with nipple discharge, most frequently in elderly women. On gross examination, these lesions appear as a friable or bosselated mass within a cystic space. Microscopically, they are characterized by one, or occasionally several, nodules of papillary carcinoma surrounded by a thick fibrous capsule. The histological appearance of the papillary proliferation can have any of the features described above for papillary DCIS (Figure 9). In addition, it is not uncommon to find entrapped neoplastic epithelial cells within the fibrous capsule, a feature that may be misinterpreted as frankly invasive carcinoma. Myoepithelial cells are not present in the papillae of encapsulated papillary carcinomas. A However, in contrast to papillary DCIS, in which there are myoepithelial cells at the periphery of the involved spaces, recent studies have failed to demonstrate a layer of myoepithelial cells at the periphery of the tumour nodules of encapsulated papillary carcinomas 11,12 (Figure 10). This observation raises the possibility that these lesions, long considered variants of DCIS, may in fact be a form of low-grade invasive carcinoma with an expansile growth pattern, or part of a spectrum of progression from in situ to invasive disease. 11,12 The finding of axillary lymph node metastases in patients with encapsulated papillary carcinoma that do not show evidence of frank invasive carcinoma provides further support for this concept. 13 Regardless of whether these lesions are in situ or invasive in nature, however, outcome studies have demonstrated that they are associated with an excellent prognosis with adequate local therapy alone Therefore, it is most prudent to continue to manage patients with these lesions as they are currently managed (i.e. similar to patients with DCIS) and to avoid categorization of such lesions as frankly invasive papillary carcinomas. Encapsulated papillary carcinoma may occur alone, but more often the surrounding breast tissue contains foci of low or intermediate nuclear grade DCIS, usually with a cribriform or micropapillary pattern. 11,17 Areas of unequivocal invasive carcinoma (most often invasive ductal carcinoma) may also be seen in association with encapsulated papillary carcinomas. These can range B Figure 9. Encapsulated papillary carcinoma at low (A) and medium (B) magnification. The tumour consists of a circumscribed nodule in which papillae are covered by a uniform epithelial cell population that in areas grows in a cribriform pattern. Figure 10. Encapsulated papillary carcinoma immunostained for CD10. Myoepithelial cells are not present either within the papillae or at the periphery of the nodule (note myoepithelial cell reactivity of adjacent normal duct). In this case, myoepithelial cells are also not demonstrable within or at the periphery of the lesion with antibodies to calponin, smooth muscle myosin heavy chain, p63 or cytokeratin 5 6.

7 26 L C Collins & S J Schnitt Figure 11. Focus of invasive ductal carcinoma arising in association with an encapsulated papillary carcinoma (a portion of which is seen in the upper right of this image). from microinvasive to larger foci (Figure 11). To avoid confusion with entrapped epithelium, the putative invasion should be clearly present beyond the fibrous capsule of the lesion. When frankly invasive carcinoma is present in association with an encapsulated papillary carcinoma, we believe it is most prudent to report only the size of the frankly invasive component as the tumour size for staging purposes in order to avoid overtreatment. 1 We do not take the size of the encapsulated papillary carcinoma itself into consideration in determination of the T stage. In the absence of frankly invasive carcinoma, we render a diagnosis of encapsulated papillary carcinoma and include an explanatory note stating that although recent studies have suggested that these may represent circumscribed nodules of low-grade invasive carcinoma rather than in situ lesions, they should be managed in a manner similar to DCIS. Solid papillary carcinoma Solid papillary carcinoma, also considered to be a variant of DCIS, presents in older women (seventh and eighth decades) as histologically circumscribed, solid nodules of neoplastic epithelial cells that are typically ovoid or spindle shaped and may have a streaming appearance similar to that seen in UDH. 18,19 Discrete papillae are not apparent; the underlying papillary structure is represented by a network of fibrovascular cores among the solid cellular proliferation (Figure 12). The cells may have endocrine features, with granular eosinophilic cytoplasm, fine nuclear chromatin and immunoreactivity for chromogranin and synaptophysin. Intracellular and extracellular mucin production is Figure 12. Solid papillary carcinoma. Portions of two circumscribed nodules of solid papillary carcinoma are seen. The nodules are composed of a uniform population of ovoid to spindle-shaped epithelial cells growing in a solid pattern. Fibrovascular cores are evident. a common feature, and areas of invasive mucinous carcinoma may be seen in association with these lesions. Other types of invasive carcinoma may also be seen. 19 Features that distinguish these lesions from UDH include a uniform cell population, polarization of the cells around fibrovascular cores and fenestrations, mucin production, and absence of reactivity of the neoplastic cells for CK Absence of myoepithelial cells within the cellular proliferation is characteristic. Lack of myoepithelial cells around the periphery of the neoplastic nodules has also been reported in some cases, raising the possibility that at least some of these lesions represent circum- Figure 13. Solid papillary carcinoma. Smooth muscle myosin heavy chain immunohistochemistry highlights pericytes around blood vessels in the fibrovascular cores, but no myoepithelial cells are present either within the lesion or at its periphery.

8 Papillary breast lesions 27 scribed nests of invasive carcinoma rather than variants of DCIS 19 (Figure 13). The identification in metastatic foci of tumour with a morphological appearance identical to that of solid papillary carcinomas raises further concern that some of these lesions are invasive rather than in situ carcinomas. 18,19 Nevertheless, solid papillary carcinomas have an indolent clinical course, especially when there is no associated frankly invasive carcinoma. 18,19 The role of myoepithelial cell markers in the evaluation of papillary lesions As should be apparent from the foregoing discussion, the presence and distribution of myoepithelial cells is one of the most useful features in distinguishing among the various types of papillary lesions. Since myoepithelial cells may be difficult to appreciate on routine haematoxylin and eosin (H&E)-stained sections, immunohistochemistry for myoepithelial cell markers such as smooth muscle actin, calponin, smooth muscle myosin heavy chain (SMMHC), p63 and others may be extremely useful in this setting. 1,12,21 It should be noted, however, that these markers vary in their sensitivity and specificity, and this must be kept in mind when interpreting these stains. 22 Pericytes surrounding blood vessels in the fibrovascular cores show expression of actin, calponin and SMMHC and may be misinterpreted as myoepithelial cells. Stromal myofibroblasts also express these markers to varying degrees. Thus, myofibroblasts present in juxtaposition to nodules of papillary carcinoma may be misinterpreted as myoepithelial cells, which could in turn result in the erroneous classification of an invasive lesion as an in situ process. Finally, some of the neoplastic epithelial cells in encapsulated papillary carcinomas show expression of p63, and when present at the periphery of the lesion these cells may be mistaken for myoepithelial cells. 11 In our practice, we most often use a combination of calponin, SMMHC and p63 in the evaluation of problematic papillary lesions. A summary of the distribution of myoepithelial cells within and at the periphery of intraductal papillomas, papillomas with atypia DCIS, papillary DCIS, encapsulated papillary carcinomas and solid papillary carcinomas is presented in Table 2. Papillary lesions on core needle biopsy There is universal agreement that surgical excision is required when an atypical papillary lesion or papillary carcinoma is present in a core needle biopsy specimen. Table 2. Distribution of myoepithelial cells (MEC) in papillary lesions of the breast MEC within papillae Papilloma Present Present Papilloma with atypia DCIS Absent in atypical areas; present in areas of residual benign papilloma MEC at periphery of involved spaces Present Papillary DCIS Absent Present Encapsulated papillary carcinoma Solid papillary carcinoma Absent Absent Absent May be present or absent However, the need for surgical excision in patients in whom a benign intraductal papilloma is found on core needle biopsy samples is an unresolved issue. The concern is that if an excision is not performed in such cases, areas of atypia or carcinoma may be missed in the limited sample afforded by core needle biopsy. The reported frequency of finding a worse lesion on excision (such as ADH, DCIS or invasive cancer) following a diagnosis of benign papilloma on core biopsy ranges from 0% to 25% However, the studies addressing this have been characterized by small patient numbers and potential selection bias with regard to which patients underwent surgical excision. Some studies have suggested that patients with a benign papilloma on core needle biopsy may not require excision, particularly if the imaging studies are concordant with that diagnosis. 27 Given the limitations of the available data, however, we currently recommend that patients with benign papilloma diagnosed on core needle biopsy undergo excision for complete evaluation of the lesion. Breast excision specimens containing a papillary lesion that has undergone a prior core needle biopsy often show foci of displaced epithelium within the core needle biopsy site. 30 The finding of displaced epithelial cells in the stroma may result in the erroneous diagnosis of invasive carcinoma if the possibility of epithelial displacement is not considered. This can be a particular problem when the lesion that was biopsied was papillary DCIS or an encapsulated papillary carcinoma, in which case the displaced epithelial cells will have cytological features of malignancy. In some examples of epithelial displacement, numerous nests of

9 28 L C Collins & S J Schnitt A B Figure 14. Epithelial displacement after core needle biopsy of an intraductal papilloma. A, Low-power view of excision specimen following core needle biopsy illustrates an intraductal papilloma (right) and adjacent biopsy site reaction (left). Even at this power, numerous epithelial cell nests are evident within the biopsy site. B, Higher-power view of displaced epithelial cell clusters in biopsy site. epithelium that show varying degrees of degenerative changes and, not infrequently, squamoid features may be seen in the stroma (Figure 14). When epithelial fragments or clusters are confined to the organizing haemorrhage, granulation tissue, or scar of the needle biopsy site, a diagnosis of epithelial displacement should be favoured. A diagnosis of invasive carcinoma should be considered only if epithelial cell nests are present in the stroma clearly away from the biopsy site and or have features characteristic of a recognized type of invasive cancer. This is particularly important in the absence of a prior diagnosis of invasive carcinoma. Immunohistochemistry for myoepithelial markers is of value in distinguishing between displaced epithelium and invasive carcinoma only if it demonstrates the presence of myoepithelial cells around the epithelial nests, a feature indicating a benign lesion. However, in many instances the epithelial cells alone are displaced into the stroma; therefore, absence of myoepithelial cells must not be used as evidence of an invasive process. Conclusions The evaluation of papillary lesions remains one of the most problematic areas in breast pathology. In this review, we have focused on several issues that are especially difficult or controversial. Although many papillary lesions can be accurately categorized based on examination of H&E-stained sections alone, others require the use of immunostains (in particular stains for myoepithelial markers and or CK5 6) as an adjunct to arrive at the correct diagnosis. New information about encapsulated papillary carcinomas and solid papillary carcinomas has raised questions about their nature (i.e. whether at least some of these are circumscribed nodules of low-grade invasive carcinoma rather than in situ lesions). Finally, the increasing use of core needle biopsy has raised issues about the management of patients with benign intraductal papillomas diagnosed on needle biopsy and has created new challenges for surgical pathologists who evaluate post-core needle biopsy excision specimens from patients with papillary lesions. References 1. Mulligan AM, O Malley FP. Papillary lesions of the breast: a review. Adv. Anat. Pathol. 2007; 14; Page DL, Salhany KE, Jensen RA, Dupont WD. Subsequent breast carcinoma risk after biopsy with atypia in a breast papilloma. Cancer 1996; 78; Tavassoli FA. Pathology of the breast, 2nd edn. Stamford, CT: Appleton and Lange, Elston CE, Ellis IO. The breast. Edinburgh: Churchill Livingstone, Lewis JT, Hartmann LC, Vierkant RA et al. An analysis of breast cancer risk in women with single, multiple, and atypical papilloma. Am. J. Surg. Pathol. 2006; 30; MacGrogan G, Tavassoli FA. Central atypical papillomas of the breast: a clinicopathological study of 119 cases. Virchows Arch. 2003; 443; Kraus FT, Neubecker RD. The differential diagnosis of papillary tumors of the breast. Cancer 1962; 15; Raju UB, Lee MW, Zarbo RJ, Crissman JD. Papillary neoplasia of the breast: immunohistochemically defined myoepithelial cells in the diagnosis of benign and malignant papillary breast neoplasms. Mod. Pathol. 1989; 2; Papotti M, Eusebi V, Gugliotta P, Bussolati G. Immunohistochemical analysis of benign and malignant papillary lesions of the breast. Am. J. Surg. Pathol. 1983; 7; MacGrogan G, Moinfar F, Raju U. Intraductal papillary neoplasms. In Tavassoli FA, Devilee PD eds. Pathology and genetics:

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