Papillary Lesions of the Breast - Review and Practical Issues PDF

Seminars in Diagnostic Pathology 39 (2022) 344–354 Contents lists available at ScienceDirect Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/semdp Papillary lesions of the breast – review and practical issues Yunbi Ni, Gary M Tse * Department of Anatomical and Cellular...

Seminars in Diagnostic Pathology 39 (2022) 344–354 Contents lists available at ScienceDirect Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/semdp Papillary lesions of the breast – review and practical issues Yunbi Ni, Gary M Tse * Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, China A R T I C L E I N F O A B S T R A C T Keywords: Papillary lesion Intraductal papilloma Solid papillary carcinoma Encapsulated papillary carcinoma Invasive papillary carcinoma Breast Papillary lesions of the breast represent a heterogeneous group of neoplasm featuring fibrovascular cores covered by epithelial cells with or without intervening myoepithelial cells. According to the World Health Organization classification of breast tumors, papillary lesions of the breast are further classified into intraductal papilloma (including intraductal papilloma with atypical ductal hyperplasia /ductal carcinoma in situ), papillary ductal carcinoma in situ, encapsulated papillary carcinoma, solid papillary carcinoma (in situ and invasive) and invasive papillary carcinoma. The overlapping morphological features and immunohistochemical profiles make accurate diagnosis of breast papillary lesion a challenge for pathologists. In this review, the morphological and relevant immunohistochemical features of papillary lesions are discussed, with further emphasis on some commonly encountered practical diagnostic issues. A simple diagnostic algorithm will be established. The relevant molecular characteristics will be discussed as well. Introduction Papillary lesions of the breast encompass a broad spectrum of dis­ eases ranging from benign and atypical lesions to malignant ones. They represent a heterogeneous group of neoplasm featuring fibrovascular cores covered by epithelial cells with or without intervening myoepi­ thelial cells. According to the World Health Organization classification of breast tumors,1 papillary lesions of the breast are further classified into intraductal papilloma (including intraductal papilloma with atyp­ ical ductal hyperplasia (ADH)/ductal carcinoma in situ (DCIS)), papil­ lary DCIS, encapsulated papillary carcinoma, solid papillary carcinoma (in situ and invasive) and invasive papillary carcinoma. The clinical manifestation of this group of disease varies. They can present with nipple discharge when centrally located, or as palpable masses when located near the surface or are relatively large. Deeper lesion can be revealed by ultrasound, mammography and magnetic resonance imag­ ing. Smaller lesions can also be picked up incidentally in breast biopsy or excision obtained for other reasons. The overlapping morphological features and immunohistochemical (IHC) profiles make accurate diag­ nosis of breast papillary lesion a challenge for pathologists, especially in the setting of core needle biopsy (CNB), in which the tissue for assess­ ment is a minute fraction of the lesion, and may not demonstrate the telltale architecture. In the external quality assurance scheme of the UK National Health Service Breast Screening, papillary lesions belong to the most frequently misinterpreted breast lesions, particularly basing on HE * Corresponding author. E-mail address: [email protected] (G.M. Tse). https://doi.org/10.1053/j.semdp.2022.06.001 Available online 11 June 2022 0740-2570/© 2022 Elsevier Inc. All rights reserved. sections alone.2 The diagnostic difficulty is also reflected by the increasing publications covering the diagnostic challenge of breast papillary lesions2-11 The pathogenesis of papillary lesions is still enigmatic. Although increasing numbers of genetic studies are trying to characterize their pathogenesis, the solid and distinct molecular features which are diag­ nostically useful are still lacking. In this review, the morphological and relevant IHC features of breast papillary lesions will be discussed, with further emphasis on some commonly-encountered practical diagnostic issues. A simple diagnostic algorithm will be established. The relevant molecular characteristics will be discussed as well. Invasive micropapillary carcinoma, which lacks true papillae, and tall cell carcinoma with reversed polarity, a recently-recognized separate entity included in the 5th edition of the WHO classification, will also be included, because of the potential confusing terminology and similar solid papillary growth pattern, respectively. Classification of breast papillary lesions In the 5th edition of World Health Organization classification of breast tumors,1 papillary lesions of the breast include intraductal pap­ illoma (including intraductal papilloma with ADH/DCIS), papillary DCIS, encapsulated papillary carcinoma, solid papillary carcinoma (in situ and invasive) and invasive papillary carcinoma. Invasive Y. Ni and G.M. Tse Seminars in Diagnostic Pathology 39 (2022) 344–354 micropapillary carcinoma and tall cell carcinoma with reversed polarity are grouped under invasive breast carcinoma and rare tumors, respectively. Papillary DCIS Papillary DCIS is a subtype of DCIS characterized by intraductal filiform arborizing fibrovascular cores devoid of myoepithelium and are lined by neoplastic ductal epithelium, while the myoepithelial cells are retained at the periphery of the involved ducts (Fig. 3). It usually rep­ resents one of several architectural patterns in a case of DCIS, rarely being the only constituent. Sometimes the neoplastic ductal epithelial cells partially or completely fill the space between the papillae, creating different geometric patterns, including cribriform, solid, micropapillary, or compact columnar patterns that may obscure the underlying papillary architecture. The tumor cells are usually of low or intermediate nuclear grade, but sometimes high grade papillary DCIS cases may be noted.17 A dimorphic variant has been reported,18 with a second population of epithelial cells showing clear cell morphology, reminiscent of myoepi­ thelial cells; negative immunoreactivity with myoepithelial markers is helpful in defining their lineage. The clinical behavior of papillary DCIS is similar with other variants of grade-matched DCIS. Intraductal papilloma Intraductal papilloma (Fig. 1) is a common benign papillary lesion, accounting for 5% of benign breast lesions,12 while patients may carry 2–3 fold increase in the risk of developing breast carcinoma. It arises from either central large lactiferous ducts as a solitary lesion, or pe­ riphery terminal duct lobular units as multiple lesions.6 Both the central and periphery intraductal papillomas are characterized by circum­ scribed intraductal proliferation consisting of arborizing fibrovascular cores lined by outer layer of luminal cells and an inner layer of myoe­ pithelial cells. As the lesion is intraductal in origin, myoepithelial cells are always present at the periphery of the involved ducts. Frequently accompanying change includes usual ductal hyperplasia and apocrine metaplasia, and less commonly or rarely are infarction, squamous metaplasia, mucinous change, clear cell change, sebaceous metaplasia and collagenous spherulosis.13,14 The superimposed usual ductal hy­ perplasia in intraductal papilloma features heterogeneous epithelial cells proliferation forming irregular or slit-like secondary lumen mainly located at the periphery of the involved ducts, which may also show stromal sclerosis and hyalinization, and the usage of IHC to identify an attenuated myoepithelial cell layer will be useful in the diagnosis. It is considered that fibrovascular cores of intraductal papilloma are gener­ ally broad and fibrotic compared with those of papillary carcinoma, although the latter may harbor broad fibrovascular cores rarely.15 Sometimes the myoepithelial cells are inconspicuous but they can be highlighted by myoepithelial cells markers. Encapsulated papillary carcinoma Encapsulated papillary carcinoma is characterized by tumor with round and pushing border typically surrounded by fibrous capsule of variable thickness (Fig. 4A). The tumor is composed of multiple delicate fibrovascular cores lined by neoplastic epithelial cells of low to inter­ mediate nuclear grade, and the epithelial cells are arranged in single or multiple cell layers, and forming micropapillary or cribriform structures filling the space between papillae (Fig. 4B). Myoepithelial cells are typically absent along the papillae as well as at the periphery of the lesion (Fig. 4C), although the latter occasional shows attenuated myoepithelial cells. Although majority of encapsulated papillary carcinoma show low to intermediate grade nuclear features, a subset of high grade encapsulated papillary carcinoma has been reported, with a prevalence ranging from 2.5 to 14% in different cohorts.19-22 These tumors are often hormonal receptors negative, tend to be of larger size, and are more frequently associated with stromal invasion.23 In a study of 10 patients with follow-up data, one with pure high grade encapsulated papillary carci­ noma developed recurrence and died of the disease23 Intraductal papilloma with ADH or DCIS Intraductal papilloma may be complicated by ADH (Fig. 2) or DCIS, characterized by focal proliferation of monotonous cells with both his­ tological features and immune profile of low grade ductal neoplasia. In this area, myoepithelial cells may be sparse or absent. The distinction between these two remains an issue of debate. An arbitrary size criterion of 3 mm, initially proposed by Page16 was adopted as a pragmatic guideline in differentiating intraductal papilloma with ADH from low grade DCIS, in spite of limited scientific evidence. The diagnosis of in­ termediate and high grade DCIS within a papilloma should be made irrespective of the extent of proliferation of epithelial cells of interme­ diate or high nuclear grade.10 Intraductal papilloma with ADH/DCIS is associated with 5 to 7 fold increase in the risk of developing invasive breast carcinoma. Solid papillary carcinoma Solid papillary carcinoma is composed of multiple expansile solid cellular nodules punctuated by thin fibrovascular cores (Fig. 5A). Generally, tumor cells are monotonous in round, oval, plasmacytoid or spindle shape with low to intermediate grade nuclear atypia. Cytoplasm ranges from pale and amphophilic to eosinophilic and granular, indi­ cating neuroendocrine differentiation (Fig. 5B-C). Intracellular and extracellular mucin are common and signet ring cells are occasionally Fig. 1. A. Low power view of intraductal papilloma. B. Intraductal proliferation consisting of arborizing fibrovascular cores lined by outer layer of luminal cells and an inner layer of myoepithelial cells. A focus of superimposed usual ductal hyperplasia is present. B. Immunohistochemical staining of p63 highlights the myoe­ pithelial cells in the fibrovascular cores and at the periphery of the lesion. 345 Y. Ni and G.M. Tse Seminars in Diagnostic Pathology 39 (2022) 344–354 Fig. 2. A. Intraductal papilloma with atypical ductal hyperplasia. The atypical cells are monotonous and they form micropapillae and rigid secondary lumen. The size of the atypical cell proliferation measures 2.5 mm. B. Immunohistochemical staining of p63 highlights the myoepithelial cells in the fibrovascular cores and at the periphery of the lesion. Fig. 3. Papillary ductal carcinoma in situ is characterized by intraductal arborizing fibrovascular cores devoid of myoepithelium and lined by neoplastic ductal epithelium, while the myoepithelial cells are retained at the periphery of the involved duct. observed (Fig. 5D). Cellular palisading around fibrovascular cores is common. Streaming growth pattern is frequently seen in cases with spindle cells. Microcystic spaces are occasionally present. Frequently, the solid cellular nodules lack surrounding myoepithelial cells. Solid papillary carcinoma in situ is diagnosed when the solid nodules have smooth rounded contours, regardless of retained, attenuated or absence of the myoepithelial cells at the periphery. Solid papillary car­ cinoma in situ may be mimicked by DCIS extensively involving a preexisting intraductal papilloma in a solid pattern in low power field. However, the underlying intraductal papilloma is still perceivable under careful scrutiny in the latter, morphologically or in conjunction with IHC which will be addressed later, and it is less likely to create diagnostic confusion in most of the cases. On the other hand, both of them are treated as in situ lesion, and the distinguishing rarely cause clinical is­ sues in terms of management differences. Solid papillary carcinoma in situ is commonly associated with invasion (Fig. 6). The rare form of invasive solid papillary carcinoma is formally defined in the 5th edition of the WHO Classification of Breast Tumors,24 346 Y. Ni and G.M. Tse Seminars in Diagnostic Pathology 39 (2022) 344–354 Fig. 4. A. Low power view of encapsulated papillary carcinoma. B. Encapsulated papillary carcinoma is characterized by tumor with round and pushing border surrounded by fibrous capsule. The tumor is composed of delicate fibrovascular cores lined by neoplastic epithelial cells of low to intermediate nuclear grade, and the epithelial cells form cribriform structures filling the space between papillae. C. Immunohistochemical staining of p63 shows the absence of myoepithelial cells along the papillae as well as at the periphery of the lesion. Fig. 5. A. Low power view of solid papillary carcinoma in situ in a multinodular pattern. B. Solid papillary carcinoma in situ is characterized by solid cellular nodule punctuated by thin fibrovascular cores. Tumor cells are monotonous in plasmacytoid morphology, and they show eosinophilic granular cytoplasm, indicating neuroendocrine differentiation. C. Immunohistochemical staining of synaptophysin reveals the neuroendocrine differentiation. D. Intracellular mucin is observed in solid papillary carcinoma in situ. as neoplastic nodules with ragged contours and devoid of myoepithelial cells forming geographical jigsaw pattern with a desmoplastic stroma. This invasive solid papillary pattern can be pure, but more frequently to be associated with in situ solid papillary carcinoma and conventional invasive carcinoma25 frankly invasive growth pattern predominantly in papillary architec­ ture.26 The invasive tumor cells form dilated ducts and microcysts containing arborizing papillae. Myoepithelial cells are absent both along the fibrovascular stalk and at the periphery. Same with other invasive breast cancer, invasive papillary carcinoma is graded according to the Nottingham grading system, and only the presence of true glands lined by polarized tumor cells with central lumen is considered as tubule formation. Majority of the previously reported cases are actually not genuine invasive papillary carcinoma but encapsulated papillary Invasive papillary carcinoma Invasive papillary carcinoma is a rare subtype of carcinoma with 347 Y. Ni and G.M. Tse Seminars in Diagnostic Pathology 39 (2022) 344–354 Fig. 6. A. Solid papillary carcinoma in situ (lower part) with adjacent invasion (upper part). B. The invasive nests are irregular and infiltrating the fatty tissue. carcinoma or solid papillary carcinoma with invasion. Due to its rarity and nonunified diagnostic criteria in studies, little is known about the true clinical behavior of invasive papillary carcinoma. A recent study with 44 cases of invasive papillary carcinoma showed that around 72% of the cases are positive for ER and PR, and 13% of them have HER2 overexpression. Comparing with infiltrating ductal carcinoma (IDC) diagnosed in the same period, invasive papillary car­ cinoma showed a favorable pathological profile than IDC, namely lower T-stage, lower Ki67 index, less axillary metastasis, higher PR expression and lower HER2 expression.27 The findings need to be verified in larger cohorts. Invasive papillary carcinoma needs to be differentiated with meta­ static carcinoma showing papillary architecture from extramammary sites, including but not limit to adenocarcinoma of lung, thyroid papil­ lary carcinoma and ovarian serous carcinoma. Relevant clinical history, in conjunction with IHC markers, is helpful in the diagnosis. apical surface abutting the epithelial-stromal interface. The empty spaces mimic lymphatic vessels, but they are not lined by endothelial cells. Nuclear grade of tumor cells is frequently intermediate or high. True angiolymphatic invasion is very common. Rarely tumor cell ag­ gregates are floating in extracellular mucin pools, constituting an aggressive variant of mucinous carcinoma28 The unique inside out pattern can be highlighted by immunohisto­ chemical staining of EMA (MUC1), which lines the periphery stromafacing surfacing of the invasive micropapillary carcinoma, but the inner luminal side of other invasive breast carcinoma. EMA (MUC1) is not recommended as a routine marker for invasive micropapillary car­ cinoma, but is only used in challenging cases. Invasive micropapillary morphology is associated with frequent lymphovascular permeation and lymph nodes involvement, but whether it is an independent prognostic factor is controversial. A meta analysis showed that presence of micropapillary carcinoma histology is an un­ favorable prognostic factor for recurrence free survival and locoregional recurrence free survival, but it does not significantly impact overall survival, disease specific survival and distant metastasis free survival29 Invasive micropapillary carcinoma Although sharing similar nomenclature, invasive micropapillary carcinoma does not contain true fibrovascular cores as papillary lesion (Fig. 7A). It is frankly invasive and composed of hollow or morula-like aggregates of cuboidal to columnar neoplastic cells surrounded by empty clear spaces formed by fibrocollagenous stroma. Tumor cells show characteristic reversed polarity, also called inside out pattern with Tall cell carcinoma with reversed polarity Tall cell carcinoma with reversed polarity is a recently recognized, separate entity.28 It shows distinct morphology as cuboidal, columnar or tall cells forming solid circumscribed nodules with thin and petite Fig. 7. A. Invasive micropapillary carcinoma is composed of hollow or morula-like aggregates of cuboidal to columnar neoplastic cells surrounded by empty clear spaces. Tumor cells show characteristic reversed polarity, also called inside out pattern. B. The basolateral staining pattern of HER2 in invasive micro­ papillary carcinoma. 348 Y. Ni and G.M. Tse Seminars in Diagnostic Pathology 39 (2022) 344–354 papillae, imparting a solid papillary growth pattern. The tumor cells contain abundant eosinophilic cytoplasm, and the nuclei are typically located away from the basal pole, giving the impression of reversed nuclear polarity. Nuclear grooves with pseudo-inclusions are variably present. Myoepithelial cells are not present throughout the whole lesion. Most of these tumors are phenotypically triple negative, although ER and PR expression in a focal and weak manner has been reported.30 In spite of mimicking the tall cell variant of papillary thyroid carcinoma, its breast origin is supported by consistent TTF-1 and thyroglobulin nega­ tivity,31 as well as variable expression of GCDFP-15, GATA-3 and mammaglobin.31-32 Tall cell carcinoma with revered polarity can also be easily differentiated with other breast papillary lesions due to its distinct morphology. This tumor is regarded as invasive, but the clinical-biological behavior is generally indolent.33 Rare cases with lymph node and bone metastases have been documented34-35 and at the periphery of the duct wall. It may be complicated by ADH/low grade DCIS. The details of differentiation will be addressed later. The absence of myoepithelial cells in the papillary fronds imply a malignant papillary lesion. The presence of myoepithelial cells at the periphery of the lesion indicates papillary DCIS, solid papillary carci­ noma, or rarely encapsulated papillary carcinoma, while their absence may occur in solid papillary carcinoma, encapsulated papillary carci­ noma or invasive papillary carcinoma. However, extramammary meta­ static carcinoma has to be excluded. The usage of HMWCK is to evaluate the nature of the solid epithelial proliferations complicating papillary lesions,37 but not the papillary areas. CK5/6 and CK14 are considered as better options.37-39 Charac­ teristically benign epithelial proliferation expresses HMWCK, whereas ADH/low grade DCIS, solid papillary carcinoma or encapsulated papil­ lary carcinoma does not. Attention should be paid to focus of apocrine metaplasia (benign), which is also negative for HMWCK. Hormonal receptor, especially ER, is also commonly used in papillary lesions. Same as HMWCK, ER is also used to differentiate benign and atypical/low grade malignancy. The former shows heterogenous ER staining while the latter reveals strong and homogeneous staining. It needs to be noted that homogeneous ER staining has also been encountered in papillomas, notably when there is columnar cell-type change seen in the lining epithelium.4 Additionally, neuroendocrine markers, including chromogranin A, synaptophysin, may be expressed in up to >40% in malignant papillary lesions39 and in specifically >90% of in situ and invasive solid papillary carcinomas.25 These markers are in general not expressed in benign papillary lesions. Practical issues in diagnosing breast papillary lesions Algorithm of diagnosing papillary lesions: in conjunction with IHC tests IHC tests have become a routine in the differentiation of different papillary lesions. The composite panel includes myoepithelial markers, high molecular weight cytokeratins (HMWCKs), and hormone receptors. The IHC phenotypes of papillary lesions are summarized by the WHO panel (Table 1).1 In general, presence of myoepithelial cells, epithelial positivity for HMWCK and heterogeneous epithelial expression of ER favor a benign intraductal papilloma. Conversely, atypical/malignant process is favored if it shows loss of myoepithelial cells, diffuse and strong epithelial expression of ER and absence of epithelial HMWCK expression. Among the commonly used myoepithelial markers, including p63, CK14, CK5/6, calponin and SMMHC, p63 is the mostly preferred one, as it shows nuclear staining and minimal cross-reactivity with stromal cells or myofibroblasts.36 Rarely the epithelial tumor cells may be stained with p6336, and they should not be misinterpreted as myoepithelial cells. Evaluation in conjunction with the morphological features is less likely to create confusion in the assessment. One additional myoepi­ thelial marker is suggested in challenging circumstance. Myoepithelial markers should be evaluated in two different compartments of papillary lesions, namely papillary fronds and periphery of the lesions. Here we proposed a simple diagnostic algorithm of breast papillary lesion basing on assessing presence of myoepithelial cells and their location in conjunction with IHC tests (Fig. 8). Intraductal papilloma has the readily demonstrable myoepithelial layer both at the papillary fronds Practical issues related with core needle biopsy Core needle biopsy (CNB) is currently a routine diagnostic procedure for majority of breast lesions, including papillary lesions. It is well established that CNB detected papillary carcinoma needs to be surgically excised, and atypical papillary lesions also need to be excised to deter­ mine whether a more significant lesion is present. However, the man­ agement of CNB diagnosed benign papillary lesions is more controversial. An upgrading rate ranging from 3% to 33% in surgical excision or imaging follow-up have been reported on CNB-diagnosed benign papillary lesions by groups of studies.40-51 A previous meta-analysis including more than 2000 cases reported an underesti­ mation rate of 15.7% in papillary lesions with core needle biopsy.52 More recent series seemed to indicate a lower rate (<2%) of upgrade to Table 1 Immunohistochemical characteristics of breast papillary neoplasms (adapted from breast tumours, WHO classification of breast tumours, 2019). Neoplasm Myoepithelial markers (e.g. p63, CK14, SMM, calponin) Papillary fronds Periphery of the lesion High-molecular-weight cytokeratins (CK5/6, CK14) ER and PR lntraductal papilloma Positive Positive Positive (heterogeneous): luminal cells, UDH Negative: apocrine metaplasia Papilloma with ADH or DCIS Positive in the papilloma; may be scant in the ADH/ DCIS component Negative; attenuated layer in rare cases Negative Positive Usually negative Positive: myoepithelial cells, UDH (heterogeneous positivity) Negative: apocrine metaplasia Positive: myoepithelial cells, UDH (heterogeneous positivity) Negative: apocrine metaplasia, ADH/DCIS Positive: myoepithelial cells Negative: neoplastic cell population Negative in the neoplastic cell population Negative or positive Negative or positive Negative in the neoplastic cell population Positive (strong and diffuse) Negative Negative Negative Positive Papillary DCISa Encapsulated papillary carcinoma Solid papillary carcinoma Invasive papillary carcinoma a Positive Positive (strong and diffuse): ADH/DCIS Positive (heterogeneous): luminal cells, UDH Negative: apocrine metaplasia Positive (strong and diffuse) Positive (strong and diffuse) High-grade lesions may show a different pattern of staining ADH, atypical ductal hyperplasia; DCIS, ductal carcinoma in situ; UDH, usual ductal hyperplasia. 349 Other Frequent chromogranin and synaptophysin expression Y. Ni and G.M. Tse Seminars in Diagnostic Pathology 39 (2022) 344–354 Fig. 8. Diagnostic algorithm of breast papillary lesions. (MEC, myoepithelial cells; ADH, atypical ductal hyperplasia; DCIS, ductal carcinoma in situ; IHC, immunohistochemistry). carcinoma at excision of asymptomatic and concordant intraductal papilloma53 For this group of biopsy-diagnosed benign lesion, some authors have recommended surgical excision, whereas others have suggested close imaging follow-up, rather than invasive surgical procedures. In 2018, the Second International Consensus Conference on lesions of uncertain malignant potential in the breast categorized benign papillary lesions in biopsies as lesions of uncertain malignant potential or B3 on a 5 scale, regardless of the presence of cellular atypia, and the consensus is that surveillance is appropriate for intraductal papillomas fully removed by vacuum assisted biopsy (VAB). Larger lesions which cannot be completely removed by VAB need open surgery and postoperative sur­ veillance. In contrast, small papillomas less than 2 mm may be coded as B2 on a 5 scale or benign, if no atypia is present and if in toto removal.54 The arbitrary size criterion of 3 mm may be problematic in differ­ entiating intraductal papilloma with ADH from low grade DCIS in CNB, as the entire lesion cannot be appreciated. In our practice, a comment will be made to the clinician that ADH might be upgraded to low grade DCIS in the completely excised specimen if the lesion involvement is more extensive. It is also true that the 3 mm size cut-off is not always easy to apply in CNB. As discussed previously, both CNB detected pap­ illoma with ADH and papilloma with low grade DCIS need to be excised, which make the accurate distinction between these two in challenging CNB is of arguable clinical significance. Another issue related with CNB is the highly fragmented sampling, due to the friable nature of papillary lesions. One may encounter de­ tached carcinoma fragments with papillary architecture and lacking attached stroma, or tumor fragments with scanty associated stroma where the lining myoepithelial cells are attenuated or lost. In this sce­ nario, it is hard to accurately assess the presence of myoepithelial cells, and the wide differential spectrum ranges from in situ to invasive papillary malignancy, including papillary DCIS, solid papillary carci­ noma, encapsulated papillary carcinoma, invasive papillary carcinoma, and less commonly metastatic carcinoma with papillary architecture from extramammary sites. Exclusion of metastasis is important to pre­ vent unnecessary surgery. The possible origins in this scenario include but not limited to adenocarcinoma of lung, thyroid papillary carcinoma and ovarian serous carcinoma. Relevant clinical history and assessing the expression of IHC markers including ER, PR, GATA-3, TTF-1, thyroglobulin, PAX-8 and WT-1, are helpful in identifying the origin of the tumor. When metastases are ruled out, the invasion of the lesion can be worked out with more certainty with the excision specimen. epithelial clusters (Fig. 9A) usually show smooth contours and are aligned in the direction of the fibroblasts and collagen bundles. Myoe­ pithelial cells (Fig. 9B), which can be highlighted by IHC staining, are always preserved, although sometime attenuated or focally lost, at the periphery of the entrapped epithelial nests. For true invasion, the invasive foci infiltrate into and not along the direction the fibrous stroma but in different directions, with the myoepithelial cells being absent. Another common mimicker is displacement of epithelial cells resulting from previous needling procedures due to the inherently friable nature of papillary lesion. Mechanical dislodgement can occur in any papillary lesions, from benign papilloma, DCIS involving papilloma, to papillary DCIS and encapsulated papillary carcinoma.56,57 IHC staining for myoepithelial cells is not helpful in this setting. The clue for differentiation is the presence of biopsy site change, including stromal and intraductal hemorrhage, hemosiderin-laden macrophages, granu­ lation tissue, fat necrosis, inflammation, and foreign-body giant cell reaction55,56 (Fig. 10). It is suggested that a diagnosis of invasive car­ cinoma 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.3 Sometimes dis­ tinguishing invasive solid papillary carcinoma versus multinodular solid papillary carcinoma in situ can also be a dilemma, as the features for invasion, namely jigsaw pattern and desmoplastic stroma are not always easily applied in the real practice. This is especially true in excision specimens after core biopsy, which can cause disruption, irregularity of the tumor nodules, and displacement, mimicking invasive lesion. One needs to consider the possibility of biopsy artifact when diagnosing invasive solid papillary carcinoma in an excisional specimen with prior procedure. The biopsy associated change mentioned as above are the hints. Practical issues of encapsulated papillary carcinoma and solid papillary carcinoma in resection specimen As mentioned previously, co-existing invasive lesion may be identi­ fied in encapsulated papillary carcinoma and solid papillary carcinoma. Gross specimens of such cases should be meticulously sampled to rule out associated invasive component, and if practical, the entire specimen is to be examined. For large specimens, representative blocks from the entire tumor including the center and periphery should be taken. It is anticipated that larger lesions have a greater probability of invasive cancer being present. Defining the minimal number of blocks that should be taken remains unclear, however it is recommended that one to two block per 10 mm of the maximum dimension of the lesion as the practice in large DCIS.58 For encapsulated papillary carcinoma, the capsule with adjacent breast tissue should be meticulously sampled and examined for the invasion beyond the capsule. True invasion and its mimics in papillary lesion True invasion has to be differentiated from benign epithelial nests entrapped in the fibrotic area of papilloma.55 The entrapped benign 350 Y. Ni and G.M. Tse Seminars in Diagnostic Pathology 39 (2022) 344–354 Fig. 9. A. Entrapped benign epithelial clusters are noted in the fibrotic area of intraductal papilloma. They show smooth contours and flow in the direction of the fibroblasts and collagen bundles. B. Immunohistochemical staining of p63 highlights myoepithelial cells surrounding these entrapped benign epithelial nests. Fig. 10. A. Intraductal papilloma (right lower) with epithelial displacement (left upper) resulting from previous biopsy. B. The displaced epithelial cells are asso­ ciated with inflamed granulation tissue, fat necrosis and hemorrhage. The exact biological nature of encapsulated papillary carcinoma re­ mains unsettled. Lacking myoepithelial cells at the periphery may sug­ gest an invasive carcinoma.59 Intact ICH staining of collagen type IV, one of the constitutes of the basement membrane, was demonstrated in all the 26 cases in one series,21 suggesting its similarity with an in situ neoplasm. Variable results are also demonstrated by genetic studies. Although less genomically complex, similar patterns of copy number aberrations were demonstrated by encapsulated papillary carcinoma and grade and ER status matched invasive ductal carcinoma,60 whereas others suggested encapsulated papillary carcinoma is genetically closer to DCIS than to invasive ductal carcinoma.61 By comparison of the invasion-associated markers expression, including matrix metal­ loproteinases, transforming growth factor receptor beta, vascular endothelial growth factor (VEGF) and E-cadherin, among encapsulated papillary carcinoma, DCIS and invasive carcinoma, encapsulated papillary carcinoma exhibits an intermediate expression pattern be­ tween the two.62 Regarding the clinical behavior, in the absence of frank invasive carcinoma, encapsulated papillary carcinoma has a favorable prognosis with adequate local excision. Lymph node metastasis is rare, occurring in less than 3% of cases.11,20 For comparison, the nodal met­ astatic rate of DCIS with no evidence of invasion was up to 7%.63 Regardless of its true biological nature, the general consensus is that in the absence of frank invasion beyond the fibrous capsule, encapsulated papillary carcinoma with low to intermediate grade nuclear features should be staged as pTis(DCIS), in order to prevent overtreatment. High grade encapsulated papillary carcinoma should be staged and managed as invasive breast carcinoma, basing on established clinicopathological parameters23 Solid papillary carcinoma, when pure is consistent with an in situ process and staged as pTis (DCIS) when the nodules have round and well-circumscribed contours, regardless of the presence of myoepithelial cells at the periphery, and so far no lymph node or distant metastasis is reported in the literature.25, 64-67 Solid papillary carcinoma is commonly associated with invasion, in the form of infiltrating ductal carcinoma of no special type (NST), lobular carcinoma, tubular carcinoma, or mucinous carcinoma, in a prevalence ranging from 27% to 81% in variable studies.25, 64-67 It is staged according to the invasive component only. HER2 interpretation in invasive micropapillary carcinoma The distinct morphology imparts a special staining pattern of HER2 in invasive micropapillary carcinoma. In a large cohort composed of 187 cases of invasive micropapillary carcinoma,68 the predominant staining pattern is basolateral membranous staining (49%, 91/187 cases). For those HER2 IHC equivocal/fluoresce in situ hybridization (FISH) amplified cases, majority of them (76%, 13/17 cases) show either entirely or a predominantly basolateral staining pattern. Previous 351 Y. Ni and G.M. Tse Seminars in Diagnostic Pathology 39 (2022) 344–354 studies also addressed this great discrepancy between HER2 IHC and FISH studies. In general, most studies demonstrated that basolateral membrane staining, irrespectively of the intensity, may represent genuine HER amplification as demonstrated by FISH.69-71 The 2018 ASCO/CAP guideline71 acknowledged this rare IHC staining patterns of HER2 and recommended such to be considered IHC 2+ equivocal and reflexed to in situ hybridization testing. Conclusion Papillary lesions of the breast encompass a broad spectrum of dis­ eases ranging from benign and atypical lesion to malignant ones. The overlapping morphological features and IHC profiles make accurate diagnosis of breast papillary lesion a challenge for pathologists, espe­ cially in the modality of core needle biopsy. Awareness of the practical diagnostic issues and careful morphological examination, in conjunction with relevant clinical history and IHC tests, including myoepithelial markers, HMWCK and hormonal receptors, are helpful in improving the diagnostic accuracy. Genetic studies have been increasingly conducted to reveal the molecular aberrations of papillary lesions, shedding light on differential diagnosis, although solid and distinct molecular features which are diagnostically useful are still lacking in most of the diseases. Molecular signatures of papillary lesions The pathogenesis of papillary lesions remains an enigmatic issue. Many genetic studies have been conducted to reveal the molecular ab­ errations of papillary lesion, shedding light on differential diagnosis, although solid and distinct molecular features which are diagnostically useful are still lacking. The early molecular study demonstrated monoclonality of benign papillomas, suggesting a neoplastic process.72 Mutations of PIK3CA and/or AKT-1, the central players in the oncogenic phosphatidylinositol 3-kinase/AKT pathway related to cell proliferation, survival, angio­ genesis, and mortality, are frequently reported in benign papilloma in a prevalence from 20 to 30%, but less commonly in papillary carci­ nomas.73-75 Similar frequencies of loss of heterozygosity (LOH) at chromosome 16p13 and 16q21 were identified in both intraductal papillomas (60%) and papillary carcinomas (63%).76 In a recent study, copy number aberration (CNA) and/or targeted mutation analysis was conducted in 44 cases of intraductal papilloma, with 20 of them showing co-existing DCIS, papillary DCIS or invasive ductal carcinoma. In these 20 cases, 55% (11/20) of the intraductal papilloma are clonally related to the synchronous DCIS and invasive ductal carcinoma, termed clonal intraductal papilloma. It was found that pure intraductal papilloma does not that commonly have CNA (37%, 9/24 cases), and the aberration predominantly involves a single CN event (67%, 6/9 cases). CNAs in any of chromosomes 1, 16 or 11 are significantly enriched in clonal intra­ ductal papilloma compared to pure and non-clonal intraductal papil­ loma. Intraductal papilloma frequently harbors activating PIK3CA mutation (69%, 9/13 cases), which is only detected in 30% of non-clonal intraductal papilloma (2/6 cases) and absent in the clonal intraductal papilloma (0/7 cases). These findings imply absence of PIK3CA muta­ tion and presence of CNA are important molecular events in the ma­ lignant progression of intraductal papilloma. The combination of wild type PIK3CA and presence of CNAs in intraductal papilloma is suggested to be clinically helpful to identify patients at high risk of progression to carcinoma77 Gene profiling on a cohort of encapsulated papillary carcinoma and solid papillary carcinoma demonstrated that most of them (90.9%, 10/ 11 cases) could be classified as the luminal subtype, with only one case being of the basal-like subtype.78 In comparison with grade and ER status matched invasive ductal carcinoma, encapsulated papillary car­ cinoma and solid papillary carcinoma are less genomically complex, but they display similar patterns of CNA.79 PIK3CA mutation, more likely to be observed in ER-positive infiltrating ductal carcinoma-NSTs, and potentially associated with good prognosis, is harbored in 40% of papillary carcinoma.79 Another study demonstrated the overall molec­ ular change in encapsulated papillary carcinoma is closer to DCIS than to invasive ductal carcinoma, which may explain its indolent behavior.80 A recent study compared the genotypic and transcriptomic profile of encapsulated papillary carcinoma with and without invasion, an overlap was found between these two, while the latter is enriched in stromal-related genes, implicating a switch to infiltrating ductal carcioma81 Tall cell carcinoma with reversed polarity is characterized by highly recurrent IDH2 mutation in 84% of the cases and PIK3CA mutation in 68% of the cases,34, 82-85 less common PRUNE2 mutation and ATM mutation have also been reported.30,83 Although mimicking the tall cell variant of papillary thyroid carcinoma, tall cell carcinoma with reversed polarity dose not harbor BRAF V600E mutation. 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