1. Benign Papillary Lesions: Papilloma
The incidence of these lesions is difficult to establish due to the lack of consistent terminology. Haagensen estimated that they represented less than 10% of benign breast biopsies [1, 2] . In 1984, Ohuchi and co-workers, using semi-serial sectioning in a series of surgical specimens from 15 patients with indraductal papilloma, identified central papillomas and peripheral papillomas [3].

Central papillomas can occur at any age with a peak incidence in the fourth and fifth decades [2, 4] . They are associated in 70% of the cases with a unilateral sanguineous or sero-sanguineous nipple discharge [5]. Specific mammographic, sonographic and galactographic features characterize them. Central papillomas are most often single and originate in the large ducts such as the segmental or sub segmental ducts, but do not involve the terminal ductal-lobular unit (TDLU) [3].

Peripheral papillomas are often clinically occult or can be discovered on mammography in the form of microcalcificatons or nodular masses. Peripheral papillomas are usually multiple and have roots in the TDLU from where they spread into the large ducts. The term microscopic papillomas is used to designate small peripheral papillomas located in adenosis and which are very often incidental findings.

The distinction between central and peripheral papillomas is not vain for peripheral papillomas are more often associated than central papilloma with DCIS and invasive carcinoma. In another three-dimensional reconstruction study of 25 surgical cases with intraductal papilloma, Ohuchi and colleagues found that six of 16 patients with peripheral papilloma had associated carcinoma compared to none of nine patients with central papilloma [6].

Microscopically, benign papillomas are made of aborescent fronds developed in expanded ductal or cystic structures. These fronds are usually less numerous and more blunt than those found in intracystic papillary carcinoma. The fronds found in benign papillomas are made of a central fibrovascular core covered by a myoepithelial cell layer underlying an epithelial cell layer. Secondary glandular structures with the basic myoepithelial/epithelial cell layers proliferating within enlarged cores are often admixed with the papillary fronds creating a mixed adenomatous and papillary pattern. Benign papillomas are subject to a number of metaplastic and inflammatory changes originating in morphological heterogeneity.

Inflammation:
Papillomas represent an obstacle in the galactophoric system inducing upstream and downstream ductal dilatation associated with periductal inflammation. This phenomenon is particularly acute in the wall of the duct harboring the papillary lesion. Parietal thickening due to inflammation and fibrosis often causes entrapment of epithelial structures within the wall producing misleading images of pseudo invasion. Analysis of such images should be integrated in the context of a benign papillary lesion to avoid a misdiagnosis of invasive or micro invasive carcinoma. Furthermore the entrapped epithelial structures retain a myoepithelial cell layer that can be identified by immunohistochemistry (SMA, P63, CK5/6).

Necrosis:
Papillomas can undergo total or partial ischemic necrosis very often associated with squamous metaplasia of the remaining epithelium [7]. Ischemic necrosis can be distinguished from tumoral necrosis; the former involves the fibrovascular core as well as the myoepithelial and epithelial lining whereas the latter is present in the epithelial compartment only.

Metaplasia:
Apocrin metaplasia and hyperplasia are very common; the latter may cause diagnostic difficulties especially if apocrin hyperplasia is florid. The same criteria as those used in the breast proper should be used to differentiate apocrin hyperplasia from atypical apocrine hyperplasia [8]. Other forms of epithelial metaplasia are occasionally encountered such as sebaceous [9], clear cell or muciparous. Osteochondromatous metaplasia of the fibrovascular cores can also occur.

Hyperplasia:
Usual ductal hyperplasia (UDH) involving papillomas has the same diagnostic features than in the breast proper. Very often it is florid filling the spaces between papillary fronds. Cell streaming, nuclear heterogeneity and nuclear overlapping, inconspicuous cellular membranes, slit like spaces, among other criteria, help distinguish UDH from epithelial neoplasia. Gynecomastoid hyperplasia is a form of micropapillary hyperplasia that can occur in benign papillomas growing from the papillary fronds or on the inner lining of the wall of the papilloma. Gynecomastoid micropapillae are made of non-polarized epithelial cells with nuclei identical to those found in UDH. Cells at the tips of the micropapillae tend to be smaller with darker staining nuclei than those found at the base of the micropapillary structures [10]. Such structures should not be confused with neoplastic micropapillary structures found in atypical ductal hyperplasia (ADH) or low grade DCIS. Recently, Otterbach et al, using immunohistochemistry with an antibody specific for cytokeratins 5 and 6 (CK5/6) were able to easily distinguish UDH (CK5/6 strongly positive) from ADH and low grade DCIS (CK5/6 negative or focally and faintly positive) in papillary lesions [11]. CK5/6 are high molecular weight cytokeratins that are strongly expressed in UDH but are down regulated in ADH and low grade DCIS [12]. Epithelial necrosis within UDH can be encountered in benign papillomas as well as nipple papillomatosis. The presence of this feature should not lead to an erroneous diagnosis of Ductal carcinoma in situ (DCIS) and should be interpreted in the light of the morphology of the surrounding epithelial proliferation.

Prognostic significance of papilloma
A benign papilloma without surrounding changes is associated with a slightly increased risk of subsequent invasive breast carcinoma, similar to that of moderate or florid usual ductal hyperplasia [13]. The standard treatment for papillomas is complete excision with microscopic assessment of surrounding breast tissue. The management of lesions diagnosed as papilloma on core needle biopsy is subject to controversy. Some authors advocate no further investigations [14] while others recommend excision for all papillary lesions, including those with completely benign features [15].

2. Atypical Papillomas
Epithelial atypia occurring in a papilloma represents for many pathologists a diagnostic dilemma in terms of recognition, denomination, assessment of subsequent breast cancer risk and management. Until recently, very few studies have specifically addressed this problem and comparison of the different findings is hampered by differences in definitions and terminologies used.

Epithelial atypia in a papilloma appears to be a rare event, although scarce data is available. Eight of the 122 (6.5%) papillomas in the study of Page et al. presented with atypical features [16] . Atypia is more frequently observed in peripheral papillomas, compared to central papilloma.

When speaking of epithelial atypia occurring in a papilloma one specifically implies the discovery, within a benign papilloma, of an epithelial cell proliferation showing the morphologic characteristics of ADH as defined elsewhere in the breast, i.e. an epithelial proliferation showing features approaching but not fulfilling standard diagnostic criteria for low grade DCIS [17, 18] . Such features include low-grade nuclear atypia with either solid, cribriform, micropapillary or stratified columnar cell architectural patterns. The atypical cell population may be of ductal type, apocrine type or may show intermediate features of both cell types. An underlying myoepithelial cell layer is invariably present but may be attenuated in atypical areas as compared to the rest of the papilloma. Such atypical areas usually show a patchy distribution within the papilloma and may extend in a pagetoid fashion along the papillary fronds. No tumoral necrosis is observed. There is no consensus on what extension criteria should be used to differentiate papilloma with ADH or atypical papilloma from DCIS involving a papilloma. Page et al in their case control study on atypia in breast papillomas, used the same size criteria that is used elsewhere in the breast, namely 3mm, to differentiate ADH from low grade DCIS occurring in a papilloma [16] . However, measuring foci of atypia in a papilloma is often difficult because of the patchy distribution of such areas and their close association with other proliferative or metaplastic cell populations. We use a pragmatic approach to the problem and consider the papilloma with atypia in the context of the surrounding breast. If the low-grade neoplastic cell population partially involves and is confined within the papilloma (what is usually seen in central papillomas) we consider the diagnosis of atypical papilloma. If the low-grade neoplastic cell population involves the papilloma as well as surrounding ducts and TDLUs (what is usually seen in peripheral papillomas) we apply the size and extension criteria to differentiate ADH from DCIS involving a papilloma.

Prognostic significance of papilloma with atypia
The significance of the presence of atypia within a papilloma is still not clear and is obscured by the frequent concurrent presence of atypia within the surrounding breast parenchyma. Raju and Vertes compared 12 papillomas with ADH with 60 papillomas without ADH [19]. Among the 12 patients with atypia in their papillomas, three developed carcinoma during follow-up in the form of ipsilateral DCIS in one case, ipsilateral DCIS followed by contralateral invasive carcinoma in one case and contralateral invasive carcinoma in one case. On the other hand, one ipsilateral and two contralateral invasive carcinomas occurred among the 60 patients presenting with papillomas without atypia. They did not perform any statistical analysis in their study because of their small population. Surprisingly all of the invasive carcinomas that occurred were situated in the contralateral breast, leading the authors to conclude that papillomas with atypia are more of a risk factor for subsequent development of invasive carcinoma in the contralateral breast. Page et al performed a nested case control study on papillomas [16]. This case control study was performed on the 368 patients with benign papilloma belonging to the Nashville cohort of 5966 patients with benign breast biopsies operated on between 1950 and 1968, and subsequently followed. Among these 368 patients with benign papilloma, 31 subsequently developed invasive carcinoma (8.4%). They studied the impact of the presence of ADH in papillomas, by comparing the 31 patients with papilloma who subsequently developed invasive breast carcinoma (case group), to a random sample of 91 patients with papilloma selected from 337 patients with papilloma who did not develop invasive carcinoma (control group). They found that the relative risk for invasive carcinoma for patients with papillomas containing ADH was nine and a half times that of patients without ADH within their papillomas. Most of the invasive carcinomas in their study occurred in the ipsilateral breast as the original papilloma, leading them to conclude that the risk represented by ADH in papillomas was mainly local. In their study, six papillomas were found to contain ADH in the case group (n=31) compared to two papillomas in the control group (n=91). Interestingly, the increased relative risk for subsequent development of invasive carcinoma observed in papillomas with ADH appeared to be strongly linked to the presence of ADH in the surrounding breast since four of the six patients with ADH in their papillomas, also had ADH in the surrounding breast. More recently, MacGrogan and Tavassoli studied the prognostic impact of epithelial atypia found within 97 central papillomas [20]. After a median follow-up of 110 months, patients subsequently developed DCIS in six cases (five: same area same breast, one: other area same breast) and invasive carcinoma in four cases (two: same area same breast, one: other area same breast and one: other breast), respectively. Presence of usual ductal hyperplasia and atypical hyperplasia in the surrounding breast parenchyma were significant predictive factors for recurrence, whereas extent of atypia within the papilloma was not. The main reason for the observed low rate of significant recurrences in this series was that epithelial atypia was, in most cases, localized in a confined papillary lesion that was completely excised.

3. Non-invasive Papillary Carcinoma
Non-invasive papillary carcinoma can present in a localized form corresponding to Intracystic Papillary Carcinoma (IPC) or can be multifocal within the TDLU and correspond to the papillary type of DCIS. IPC is infrequent and represents less than 2% of breast carcinomas [21, 22, 23] . Clinically, mammographically and macroscopically, such lesions are difficult to differentiate from benign central papillomas. However, their median age at discovery (65 years) is older than that of benign papillomas and they tend to be larger.

Microscopically, IPC is made of multiple arborescent fronds developed in a cystic structure. On low magnification, the fronds are finer and more complex and branching than those observed in benign papilloma. The important feature in these lesions is the complete or near complete absence of a myoepithelial cell layer inserted between the fibrovascular cores and the epithelial cell layer as evidenced by immunohistochemistry using SMA, CK5/6, P63 or CD10 [24, 25] . Due to the complete absence of myoepithelial cells at the periphery of these lesions, some authors have questioned the in situ nature of all such lesions or if some of the cases in this category represent in fact circumscribed nodules of invasive carcinoma [26]. The neoplastic epithelial cell population in these lesions is usually of low nuclear grade and cells are organized in solid, cribriform, micropapillary or stratified columnar cell architectural patterns. However, in some cases tumor cell nuclei of moderate or high grade and tumor cell necrosis can be present. Tumor cell entrapment can be present within the wall of IPC resulting in a pseudoinvasive pattern. A definitive diagnosis of invasive carcinoma associated with IPC should only be considered when neoplastic epithelial structures infiltrate the breast beyond the fibrous wall and have one of the recognized patterns of invasive carcinoma. Lefkowitz et al. previously individualized 22 cases in a series of 77 intracystic papillary carcinomas showing dimorphic features in the form of neoplastic epithelial clear cells inserted between the fibrovascular stalks and overlying darker staining cells [27]. Due to their localization, these clear cells simulate myoepithelial cells and can cause diagnostic problems. However these cells have identical nuclear features than adjacent malignant epithelial cells and they have the same immunohistochemical profile.

Prognostic significance of non-invasive papillary carcinoma
The pathologic prognostic features of DCIS (nuclear grade, necrosis, tumor size and margin width) are also applicable to the papillary type of DCIS. Carter et al. studied a series of 41 IPCs [21]. No axillary metastases were found in the 11 patients who had axillary lymph node dissection. No distant metastases occurred in the 29 patients who underwent mastectomy. Eleven patients did not have mastectomy, or radiotherapy. One had a recurrent or persistent tumor removed three years later and two patients subsequently developed ipsilateral invasive carcinoma at three and six years of follow-up, respectively. The other patients were free of disease after a follow-up ranging from 7 to 17 years. DCIS in the surrounding breast ducts was associated with IPC in 19/41 (36%) cases. In the group of patients with conservative therapy, all the patients who subsequently developed recurrence or invasive carcinoma had DCIS, but only one of eight patients who had no further evidence of disease without treatment, had associated DCIS. In the series of 77 IPCs studied by Lefkowitz et al., 52 patients underwent mastectomy, 25 patients had excisional biopsy and 28 patients underwent axillary lymph node dissection [27]. Two axillary lymph node metastases were found in one patient. The mean follow-up interval was 11.3 years. Three patients experienced distant metastatic disease. Invasive local chest wall recurrence occurred in six patients. In this study local recurrences and distant metastases appear to be associated with nuclear grade, although no statistical analysis was performed. Solorzano et al analyzed the clinicopathologic and outcome features of 40 cases of IPC [23]. IPC alone, IPC with associated DCIS and IPC with associated invasive carcinoma were found in 14, 13 and 13 patients, respectively. Among the 28 patients who had an axillary lymph node dissection, three presented with axillary lymph node metastases and all three had associated IPC and invasive carcinoma. All patients underwent margin negative resections. After a median follow up of 52 months, one out of 14 patients with pure IPC experienced a local recurrence in the form of pure IPC, 2/13 patients with IPC + DCIS had local recurrences (one invasive papillary carcinoma and one DCIS) and 1/13 patients with IPC +DCIS had bone metastases, finally 1/13 patients with IPC + invasive carcinoma had a local recurrence in the form of invasive papillary carcinoma. This and other reports confirm the excellent prognosis associated with pure IPC. The low frequency of axillary node metastases with pure IPC does not justify axillary lymph node dissection. The role of radiation therapy in these patients remains undefined. Patients with IPC and associated DCIS and/or invasive carcinoma should be treated on the basis of the associated pathology.

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