Papillary lesions of the breast

According to the European classification system, diagnostic CNB and VAB containing fragments of intraductal papillomas are coded as B3 and, due to the histomorphological heterogeneity of papillomas, excision is recommended [7, 45, 77]. However, the upgrade rate to DCIS and invasive carcinoma after surgery is low and varies between 0 and 16% (Table 1) [13, 15, 43, 49, 52, 58, 60, 62, 66]. Recent studies investigated upgrade rates and necessity of excision versus only imaging follow-up after biopsy. High risk lesions were found in 9.5% of 327 intraductal papillary lesions undergoing excision, DCIS in 3.4%, and invasive carcinomas in 2.4% [43]. Upgrade to DCIS or invasive carcinoma was more common among women over the age of 50 years, with lesions > 1 cm, lesions presenting as palpable mass, or if the lesion was > 5 cm distant from the nipple [43]. Among 61 patients under follow-up by imaging, no cancers were detected. In another recent study, features predicting upgrade were older age (median 64 versus 55), higher BIRADS category (≥ 4), lesion size (≥ 0.5 cm), and mass lesions with calcifications [52]. It was suggested that in particular, younger women with non-mass abnormalities and low BIRADS categories may benefit from clinical and imaging follow-up alone [52]. In a recent series analyzing symptomatic cases only, a general 2.4% upgrade rate was found with an upgrade to ADH and LN of 12.1%, but no predictive features for upgrade were identified [60]. It was suggested that if the whole lesion is removed by VAB and lacks atypia, there is no need for further surgery. No upgrade to malignancy was found if the benign papillary lesion was diagnosed on 11 G VAB and followed by excision [15]. Only the presence of atypia in a papilloma and older age were associated with upgrade to malignancy. Nevertheless, long-term follow-up is recommended [8]. In summary, these studies challenge the necessity of general excision of papillomas due to low upgrade rates. In 2018, the Second International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions) concluded that surveillance is appropriate for intraductal papillomas fully removed by VAB. Larger lesions which cannot be completely removed by VAB need open surgery and postoperative surveillance. In contrast, small papillomas (< 2 mm) may be coded as B2, if no atypia is present and if in toto removal can be safely diagnosed [69]. Since multiple (more than 5) papillomas were shown to bear a threefold increased relative risk for subsequent development of breast cancer, long-term follow-up is recommended after surgical removal. The relative risk increases to sevenfold, if multiple papillomas are associated with ADH or LN [46]. We would like to suggest to use the term “papilloma with atypical ductal epithelial proliferation (ADEP)” for biopsies and to restrict “papilloma with ADH/DCIS to excision specimens.

Tall cell carcinoma with reversed polarity (TCCRP) has been formerly known as breast tumor resembling the tall cell variant of papillary thyroid carcinoma and as solid papillary carcinoma with reverse polarity. TCCRP is a rare subtype of invasive breast carcinoma consisting of tall columnar cells with reversed nuclear polarity arranged in a solid pattern. TCCRP usually presents as a well-circumscribed mass, measuring up to 5 cm in diameter.

The close resemblance to papillary thyroid carcinomas results from its frequent demonstration of papillae and follicular structures, even with colloid-like material, psammoma bodies, tumor cell nuclei with grooves and inclusions (Fig. 9). The tumor cells are tall columnar with prominent eosinophilic cytoplasm rich in mitochondria. The nuclei are located at the apical areas of the cells hence the “reversed polarity” appearance. Myoepithelial cells are almost always missing. Foamy macrophages are often present within the fibrovascular cores. TCCRP is usually triple negative or weakly ER/PR-positive but with low Ki67 labeling index. Immunohistochemistry for calretinin is usually positive and negative for synaptophysin, chromogranin A, TTF1 and thyroglobulin. GATA3, GCDFP15, and mammaglobin are variably positive [5, 83].

A characteristic hotspot mutation R172 in the IDH2 gene, which is otherwise rare in breast carcinomas, was detected in the vast majority of TCCRPs. Mutant IDH2 can be detected by immunohistochemistry using a specific antibody [94]. Other tumors harbor PRUNE2 mutations. Missense mutations affecting PIK3CA or PIK3R1 may also be detected. BRAF mutations are not encountered.

Mucinous cystadenocarcinoma (MCA) is a very rare cyst-forming invasive breast carcinoma with papillae and abundant extracellular mucin (Fig. 10). So far, less than 35 cases have been published with predominance of Asian women [90]. The low number of cases could be explained by under-recognition. MCA usually occurs in postmenopausal women as a palpable mass with a relatively large diameter being ≥ 4 cm in 50% of the cases [38]. MCA is well circumscribed and often hypoechoic on ultrasound. The typical gross appearance is a gelatinous cyst. A prominent papillary architecture with swollen fibrovascular cores is often present and the papillae show hierarchical organization. An association with mucocele-like structures is frequent. Tumor cells are columnar with basally located nuclei, tufting, stratification, and abundant mucin production. Squamous morules or floating micropapillary groups may be observed at the tip of papillary projections and are considered a useful microscopic clue to distinguish MCA from other mucinous carcinomas of the breast [82]. Nuclear atypia is variable within the same lesion [42]. When DCIS is absent, metastatic origin should be ruled out because of overlapping features with pancreatic, appendiceal, and ovarian mucinous neoplasms. A panel of immunohistochemical markers including CK7, CK20, CDX2, and GATA3 is helpful. In contrast with pure mucinous carcinoma and EPC, which typically express ER and PR, MCA is triple negative [35, 90]. The majority of MCA has been treated by radical mastectomy; data regarding the need of systemic adjuvant therapy are missing. Lymph node involvement is rare in MCA and prognosis is considered favorable. However, the low level of evidence, as well as the lack of large case series with a long-term follow-up, recommends caution regarding therapeutic conclusions [38].

Metastases from ovarian carcinomas, mucinous tumors of the GI tract, particularly the pancreas, renal cell carcinomas, lung adenocarcinoma, papillary thyroid carcinoma, and prostate ductal adenocarcinoma may show a papillary architecture and mimic a primary papillary neoplasm of the breast [44]. A case of metastatic gastrinoma mimicking SPC was reported [12]. Immunohistochemistry is helpful for differential diagnosis and may be crucial for certain cases.

Micropapillary DCIS (MP DCIS) is a pattern of DCIS characterized by the formation of micropapillae. In contrast to papillae, micropapillae lack a fibrovascular core. MP DCIS is frequently associated with “snake skin-like” microcalcification [81]. High rate of recurrence following breast conserving surgery has been reported [14].

MP DCIS is composed of low-grade neoplastic cells involving usually small and mid-sized ducts (Fig. 11). MP DCIS may occur together with other patterns of DCIS (e.g., cribriform, solid). Immunohistochemistry with high molecular weight keratins (CK5 or 14) is useful to distinguish MP DCIS from UDH with micropapillary pattern.

Invasive micropapillary carcinoma (IMPC) is characterized by clusters of cells within clear spaces showing an inside-out pattern. IMPC presents as palpable lesion with variable imaging features including frequent microcalcifications, all highly suspicious of malignancy [3, 6, 16]. With a prevalence of < 2%, pure IMPC is about four times rarer than mixed IMPC with NST [54]. Relatively small solid nests or rings of tumor cells are present in empty spaces because of detachment from the surrounding stroma mimicking retraction clefts, invasion in adipose tissue or in lymphatic vessels (Fig. 12) [2]. The apical pole is usually oriented towards the empty spaces displaying an”inside-out” or reversed polarity pattern, which can be highlighted by EMA or MUC1 immunohistochemistry [54]. Most IMPC are ER- and/or PR-positive. The reversed polarity is also reflected by the peculiar incomplete U-shaped basolateral membrane staining pattern for HER2, which challenges the current guidelines for the interpretation of HER2 immunohistochemistry [95]. Amplification of HER2 is seen in 10–30% of IMPC, while a triple negative phenotype is rare. Despite higher frequency of lymph node metastasis, higher tumor grade, and more frequent lymph vascular invasion compared to NST carcinomas, pure IMPC does not show worse prognosis [16]. A higher level of stromal tumor infiltrating lymphocytes (TILs) seems to be associated with features of dismal prognosis when compared to IMPC with low TILs, being consistent with the predominant luminal phenotype of IMPC [22]. Immunohistochemistry for GATA3, WT1, and PAX8 is useful to exclude metastasis from ovarian serous carcinoma.

IMPC does not show pathognomonic mutations or translocations but distinctive complex patterns of copy number alterations as compared to NST carcinomas, such as 16q losses and 8q, 17q, and 20q gains [55]. Amplification of MYC (8q24), CCND1, and FGFR1 genes is frequent [56]. Mutations are present in the MAPK pathway and in TP53 and PIK3CA [63]. Sporadic reports also describe mutations and deregulations in genes involved in cell polarity, shape, migration, and ciliogenesis [32].

Secretory breast carcinoma (SBC) is exceedingly rare and characterized by a pathognomonic recurrent t(12;15)(p13;q25) translocation, which results in the chimeric fusion gene ETV6-NTRK3 [84]. SBC is mostly observed in post-menopausal women although it can occur at any age and also in males [36]. SBC presents as a slowly growing mass sharing radiological features with benign lesions like papillomas [87]. A predominant papillary pattern may be observed on occasion resulting in a challenging diagnosis on CNB [80]. SBC is composed of a heterogeneous cellular component including cells with amphophilic cytoplasm, apocrine aspect or a “bubbly aspect” due to abundant intracytoplasmic secretions (Fig. 13). Eosinophilic extracellular material positive for PAS, mucicarmine, and Alcian blue is consistently present. SBC usually shows a triple negative phenotype, but low ER expression and an ER − /PR + phenotype have been observed. S100 and mammaglobin are usually positive; expression of GCDFP-15 has been debated [18, 37, 47]. Pan-TRK immunohistochemistry has been suggested as a useful tool to confirm SBC diagnosis, or may be used for the selection of patients eligible for NTRK inhibitor therapy in the metastatic setting [79, 89]. The clinical course of SBC is indolent compared to IBC-NST; however, metastatic cases have recently been described [34, 37].

Adenomyoepithelioma (AME) of the breast is characterized by an epithelial-myoepithelial phenotype with heterogeneous architecture including a predominant papillary pattern [29]. AME is very rare and occurs mainly in post-menopausal women. Radiologically, it displays lobulated dense masses with often indistinct margins [57, 67]. AME diagnosis should be restricted to cases showing a biphasic cytology with prevalent expansion and proliferation of the myoepithelial component (Fig. 14). The distinction of AME from intraductal papilloma with myoepithelial hyperplasia is important due to the different biological behavior. While myoepithelial hyperplasia is generally focal in benign papillary lesions (Fig. 15), it is diffusely expanded in papillary AME [33]. AME can be ER-positive or -negative and is characterized by a different genomic landscape (e.g., HRAS Q61 hotspot mutations in ER-negative AME) [30, 31]. The current WHO classification distinguishes between AME and malignant AME [27, 28]. However, the identification of atypical and malignant features is extremely challenging and remains a source of debate. Recently, the following detailed definitions for the distinction between AME and malignant AME were published [70]. Malignant AME in situ includes lesions with a classical AME architecture in which the epithelial component shows features of DCIS. The atypical cells show a cribriform or solid growth pattern with a well-defined margin or evidence of development within an intraductal-like structure. A peripheral myoepithelial cell layer at the epithelial stroma interface is typically seen. Malignant AME invasive (synonym: invasive adenomyoepithelial carcinoma) displays a dominant AME architecture but also has features sufficient for a diagnosis of malignancy including cytological atypia, increased mitotic activity, and necrosis associated with frankly invasive foci and an accompanying stromal response. The malignancy in these tumors can affect the luminal epithelial or the myoepithelial components or both [70].

Nipple adenoma (NA) is a benign tumor originally described as florid papillomatosis of the nipple [78]. NA occurs both in females and males with a wide age range (5 months to 89 years). Clinically, it may resemble Paget’s disease of the nipple. The dermo-epidermal junction is regarded as the site of origin. Involvement of the sub-areolar ducts with a general papillary aspect is a common feature. Histologically, a mixture of adenosis, papillary hyperplasia, and usual ductal hyperplasia is observed, frequently associated with squamous or apocrine metaplasia (Fig. 16). The presence of sclerosis may result in a pseudo-invasive growth pattern [78]. Immunohistochemistry using CK 5, ER, and myoepithelial markers helps in the differential diagnosis with DCIS or invasive carcinoma. The association with DCIS and invasive carcinoma has been rarely reported [1, 23, 91]. Mutations in PIK3CA are frequent; K-RAS and BRAF mutations may also occur [48]. Incomplete resection is associated with recurrence.

A variety of non-neoplastic lesions may show a papillary or micropapillary pattern. Among those, juvenile papillomatosis, florid gynecomastia with micropapillae-like intraductal epithelial proliferation, papillary apocrine metaplasia and UDH with papillary pattern (papillary intraductal hyperplasia) are encountered. These lesions are beyond the scope of this review and are not further discussed in detail.