Molecular alterations in lesions of anogenital mammary-like glands and their mammary counterparts including hidradenoma papilliferum, intraductal papilloma, fibroadenoma and phyllodes tumor.

Lesions affecting anogenital mammary-like glands (AGMLG) are histopathologically very similar to those seen in the breast but whether this morphological similarity is also reflected at the genetic level is unknown. To compare the underlying molecular mechanisms in lesions of AGMLG and their mammary counterparts, we analyzed the mutational profile of 16 anogenital neoplasms including 5 hidradenomas papilliferum (HP), 1 lesion with features of HP and fibroadenoma (FA), 7 FA, 3 phyllodes tumors (PhT)) and 18 analogous breast lesions (6 intraductal papillomas (IDP), 9 FA, and 3 PhT) by high-coverage next generation sequencing (NGS) using a panel comprising 50 cancer-related genes. Additionally, all cases were analyzed for the presence of a mutation in the MED12 gene. All detected mutations with allele frequencies over 20% were independently validated by Sanger sequencing (concordance: 100%). Mutations in PIK3CA, AKT1, MET, ABL1 and TP53 genes were found in lesions of AGMLG and also their mammary counterparts. The PI3K-AKT cascade plays a role in tumors arising at both sites. It appears that some histopathologically similar anogenital and breast lesions develop along similar molecular pathways.

Combined evaluation of CK5/6, ER, p63, and MUC3 for distinguishing breast intraductal papilloma from ductal carcinoma in situ.

The differentiation of intraductal papilloma (IDP) in the breast from ductal carcinoma in situ (DCIS) is sometimes difficult. Fifty papillary lesions (25 DCIS and 25 IDP) were immunohistochemically examined using a panel of antibodies, including CK5/6, ER, p63, Ki-67, chromogranin A, synaptophysin, neuron specific enolase, CD56, MUC1, MUC3, CD44, p21, p27, and p53. The immunohistochemical staining pattern of each antibody was evaluated using the Allred scoring system. Then, the area under curve (AUC) for each antibody was computed by receiver operating characteristic (ROC) analysis. DCIS typically showed high scores for ER and MUC3 reactivity compared with IDP, and the AUC for ER and MUC3 were 0.941 and 0.908, respectively. In contrast, IDP showed high scores for CK5/6 and p63 reactivity compared with DCIS, and the AUC for CK5/6 and p63 were 1.00 and 0.954, respectively. We devised a 'Differential Index' (DI) using the following formula: [S(ER) + S(MUC3)]/[S(CK5/6) + S(p63) + 1]. The distributions of the DI for IDP and DCIS did not overlap when the cutoff value was placed arbitrarily at DI = 1.0. From these results, it is concluded that a panel of four CK5/6, ER, p63, and MUC3 antibodies provide valuable information for differentiating IDP from DCIS.

Microdochectomy in the management of pathologic nipple discharge.

BACKGROUND: There is a debate in the literature whether a pathologic nipple discharge is a distinct sign of breast carcinoma. Our own results obtained by the use of microdochectomy as a minimally invasive operative procedure in 184 patients with pathologic nipple discharge were analysed. The aim of this retrospective 20-year study was to assess the efficacy of microdochectomy in detecting early stages of intraductal breast carcinoma. PATIENTS AND METHODS: The study included data on 184 patients aged 24-77 years (median 46.6) divided into two groups of premenopausal (n = 123) and postmenopausal (n = 61) women. There were 139 patients with unilateral single-duct sanguinolent discharge and 45 patients with other types of nipple discharge. The operative procedure consisted of the discharging duct excision by use of a guide probe, preceded by cytology and ductography studies. RESULTS: Histopathology of the excised ducts revealed only three carcinomas in premenopausal women and ten carcinomas in postmenopausal women. In a total of 13 carcinomas, there were 4 ductal carcinomas in situ, detected in patients aged 41-72 (median 66) years. Twelve carcinomas were associated with sanguinolent nipple discharge. Papilloma was the most common histology finding (56.5%). CONCLUSION: Results of the study suggested mainly the association of sanguinolent single-duct nipple discharge and papilloma, whereas the rate of malignancies detected (7.0%) was consistent with literature reports. Microdochectomy proved to be a highly efficient operative method free from any impairment of the breast integrity. Conservative treatment with close clinical monitoring of the patient with cytology and ultrasonographic assessment might be possible in selected cases.

[Clinicopathologic and immunohistochemical study of 187 cases of intraductal papillary neoplasm of breast].

OBJECTIVE: To evaluate the diagnostic approach and criteria for intraductal papillary neoplasms of breast. METHODS: According to the criteria of 2003 WHO classification, 187 cases of intraductal papillary neoplasm of breast were identified and enrolled into the study. The clinical and histologic features were reviewed and immunohistochemical study for CD10, p63, CK14, CK5/6, CK7, MGB1 and p53 were carried out on 53 cases. RESULTS: Amongst the 187 cases studied, there were 128 cases of intraductal papilloma, 16 cases of atypical intraductal papilloma and 43 cases of intraductal papillary carcinoma. They showed a spectrum of morphologic features including epithelial and stromal hyperplasia and secondary changes. The expression of myoepithelial markers, including CD10 and p63, significantly decreased in ascending order from intraductal papillomas, atypical intraductal papillomas and intraductal papillary carcinomas (P < 0.001). The expression of basal cell markers, including CK5/6 and CK14, showed a mosaic pattern in benign lesions and significantly decreased or was absent in atypical and carcinomatous lesions (P < 0.001). In contrast, the luminal cell marker CK7 expressed in the three groups with no statistically significant difference (P = 0.06). On the other hand, the expression of MGB1 in intraductal papillary carcinomas was much lower than that in the other two groups (P = 0.002 and P = 0.007). The staining for p53 was negative in all of the three groups. CONCLUSIONS: Intraductal papillary neoplasms of breast represent a heterogeneous group of lesions with various morphologic appearances. Correlation with immunostaining results for myoepithelial markers, basal-type cytokeratins and luminal epithelial markers are helpful in arriving at a definitive diagnosis.

Expression of LGR5 in mammary myoepithelial cells and in triple-negative breast cancers.

Lineage tracing in mice indicates that LGR5 is an adult stem cell marker in multiple organs, such as the intestine, stomach, hair follicles, ovary, and mammary glands. Despite many studies exploring the presence of LGR5 cells in human tissues, little is known about its expression profile in either human mammary tissue or pathological lesions. In this study we aim to investigate LGR5 expression in normal, benign, and malignant lesions of the human breast using RNA in situ hybridization. LGR5 expression has not been observed in normal lactiferous ducts and terminal duct lobular units, whereas LGR5-positive cells have been specifically observed in the basal myoepithelium of ducts in the regenerative tissues, ductal carcinoma in situ, and in ducts surrounded by invasive cancer cells. These findings suggest LGR5 marks facultative stem cells that are involved in post injury regeneration instead of homeostatic stem cells. LGR5 positivity was found in 3% (9 of 278 cases) of invasive breast cancers (BC), and it showed positive associations with higher histologic grades (P = 0.001) and T stages (P < 0.001), while having negative correlations with estrogen receptor (P < 0.001) and progesterone receptor (P < 0.001) expression. Remarkably, all LGR5-positive BC, except one, belong to triple-negative BC (TNBC), representing 24% (9 of 38 cases) of all of them. LGR5 histoscores have no correlations with EGFR, CK5/6, Ki-67, or P53 expression. Additionally, no ß-catenin nuclear localization was observed in LGR5-positive BC, indicating that canonical Wnt pathway activation is less likely involved in LGR5 expression in BC. Our results demonstrate that LGR5 expression is induced in regenerative conditions in the myoepithelium of human mammary ducts and that its expression is only observed in TNBC subtype among all invasive BC. Further studies regarding the functional and prognostic impact of LGR5 in TNBC are warranted.

Diagnostic evaluation of papillary lesions of the breast on core biopsy.

The management of asymptomatic intraductal papillary lesions of the breast diagnosed on core biopsy poses a challenge for patients and clinicians, as the distinction between common benign lesions and atypical or malignant varieties may be difficult without formal excision. The aim of this study was to determine whether a combination of histopathologic and biomarker features could be used to accurately identify benign papillary lesions on core biopsy. An inclusive group of 127 excised papillary lesions was characterized by detailed histopathologic review and immunohistochemical staining for the basal markers cytokeratin 5/6 (CK5/6) and P63 and the proliferation marker Ki67. Comparison of benign, atypical, and malignant lesions revealed that the combination of broad, sclerotic fibrovascular cores, and epithelial CK5/6 staining was most commonly seen in benign papillomas. Ki67 staining revealed striking intralesional heterogeneity, but there was no difference between the high scores of benign, atypical, or malignant lesions (P=0.173). In a non-overlapping set of 42 cases, a binary classifier specifying benign lesions on the basis of thick fibrovascular cores and epithelial CK5/6 staining on core biopsy gave an overall misclassification rate of 4/42 (10%) when compared with the final excision diagnosis. Misclassified cases included 2/27 lesions ultimately diagnosed as benign and 2/2 atypical papillomas. All malignant lesions (n=13) were correctly assigned. The combined assessment of fibrovascular core thickness and CK5/6 staining on core biopsy distinguished benign from malignant papillary lesions, but did not separate benign from atypical cases. This approach may form a useful addition to the clinicopathologic evaluation of papillary lesions of the breast.

Evaluation of CD56 and CD57 immunostainings for discrimination between endocrine ductal carcinoma in situ and intraductal papilloma.

Endocrine ductal carcinoma in situ (E-DCIS) is an intraductal carcinoma characterized by endocrine features and expression of neuroendocrine markers. E-DCIS and intraductal papilloma (IDP) resemble in their clinical features. However, the former is an intraductal carcinoma, and the latter is an intraductal benign lesion. It is sometimes difficult to distinguish E-DCIS from IDP because both can show near solid intraductal cellular proliferation. Discrimination between lesions is important not only histopathologically, but also clinically. This study aimed to evaluate the applicability of CD56 and CD57 for the discrimination between E-DCIS and IDP. Specimens were obtained from 17 E-DCIS patients as the subject group, and 27 IDP patients as the control group, diagnosed in St Marianna University Hospital. E-DCIS was diagnosed using Chromogranin A, Synaptophysin, and Grimelius stainings by the premise of histopathological features. These specimens were subjected to CD56, CD57 immunostainings. Staining results were compared between E-DCIS and IDP. In our study, CD56 revealed significant differences for distinguishing E-DCIS from IDP as determined by Fisher's test (cutoff: not less than 33-67%< immunopositivity, P < 0.05). We found that not only E-DCIS but also IDP revealed immunopositivity for CD56. However, it is considered that E-DCIS diagnosis is possible by diffuse immunopositivity of CD56 after having been based on histopathology.

[Fiberoptic ductoscopy in 1,025 cases of nipple discharge].

OBJECTIVE: To assess the value of fiberoptic ductoscopy (FDS) in the diagnosis of nipple discharge. METHODS: Clinical records of 1,025 patients with nipple discharge undergoing FDS from February 2006 to March 2008 were reviewed. RESULTS: There were obviously differences in the FDS diagnosis of various nipple discharge traits. The diagnosis by FDS was pathologically confirmed in 93.7%of patients with nipple discharge (404/431). CONCLUSION: FDS can effectively improve the diagnosis of nipple discharge,and has great clinical significance.

Intraductal papilloma arising from the accessory parotid gland: A case report and literature review.

RATIONALE: Intraductal papillomas of the accessory parotid glands are extremely rare benign tumors that are most commonly derived from minor salivary glands and are easily misdiagnosed as other diseases. Studying these lesions by pathology and immunohistochemistry can raise awareness of the disease, reduce the rate of misdiagnosis, and provide more precise treatments. PATIENT CONCERNS: A 35-year-old man first presented to our hospital with a 6-month history of a painless mass on his left parotid gland. DIAGNOSES: The patient was diagnosed with intraductal papilloma of the accessory parotid gland by pathology and immunohistochemistry. INTERVENTIONS: The mass was completely resected. OUTCOMES: After 2 years of postoperative follow-up, the patient recovered well without recurrence. LESSONS: Intraductal papilloma of the accessory parotid gland is very rare, and can easily be misdiagnosed as sialadenoma papilliferum, inverted ductal papilloma, or papillary cystadenoma, among others. It is necessary to analyze its pathology and immunohistochemistry in comparison with other diseases. Early excision and long-term follow-up are necessary to provide optimal treatment and to better understand the pathological processes of intraductal papilloma.

Breast Cancer Risk Associated With Benign Intraductal Papillomas Initially Diagnosed on Core Needle Biopsy.

BACKGROUND: The long-term risk for patients with benign intraductal papillomas (IDPs) on core needle biopsy (CNB) who are not upgraded on excision is not well-defined. The goal of this study was to determine the cumulative breast cancer (BC) incidence for patients with benign IDP on CNB. MATERIALS AND METHODS: There were 152 benign IDPs diagnosed on CNB between 2003 and 2008. Radiology and pathology data were reviewed by breast radiologists and pathologists. Clinical follow-up was obtained from the electronic medical record (Epic). RESULTS: Excision results were: 96 (63%) not upgraded, 9 (6%) with BC on excision (6 ductal carcinoma in situ, 3 invasive carcinoma), and 5 (3%) lacked correlation with the CNB site. Excision reports were unavailable for 42 (28%). Excluding cases with Breast Imaging Reporting and Data System (BI-RADS) 5 or discordant imaging, there were 6 (4%) true upgrades (all ductal carcinoma in situ). After the exclusion of patients with other major risk factors, follow-up was available for 55 of 58 patients with benign IDPs, and 8 (14%) developed BC after a median of 112 months (range, 11-159 months). None of the benign IDP patients without an excision report developed BC after a median of 97 months (range, 5-164 months). CONCLUSIONS: The upgrade rate for benign IDP diagnosed on CNB was 4%, similar to recent studies. The cumulative BC incidence for those who were not upgraded and who had no history of BC was 14% at a median of 9 years. When combined with patients without an excision pathology report, the overall BC incidence was 9%. The findings support continued breast cancer surveillance in this patient population.

The role of immunohistochemistry for smooth-muscle actin, p63, CD10 and cytokeratin 14 in the differential diagnosis of papillary lesions of the breast.

BACKGROUND: Histological differentiation of mammary papillary lesions can be difficult. The evaluation of myoepithelial cells can be helpful, with benign papilloma showing a continuous myoepithelial cell layer, which becomes attenuated or absent in malignant papillary lesions. METHODS: A large series of 100 papillomas (28 papillomas with florid epithelial hyperplasia) and 68 papillary carcinomas (9 invasive, 44 in situ, and 15 ductal carcinomas in situ (DCIS) involving papillomas) of the breast were stained for myoepithelial cells by immunohistochemistry using antibodies to smooth-muscle actin (SMA), p63, CD10 and cytokeratin (CK) 14. RESULTS: In the papillomas, using these four antibodies, myoepithelial cells were positive in 88%, 99%, 91% and 95% of cases, respectively, with SMA showing marked stromal component cell staining and CD10 showing epithelial and stromal staining. CK14 also showed epithelial staining in 71% of papillomas and 96% of papillomas with florid epithelial hyperplasia. In the papillary carcinomas, 36 (53%) cases showed staining of myoepithelial cells that were scattered, discontinuous and diminished in number and the remaining 32 (47%) cases did not show myoepithelial cells. Invasive papillary carcinoma has the lowest proportion (33%) with myoepithelial cells, and DCIS involving papillomas had the highest proportion (87%). CONCLUSIONS: p63 had the highest sensitivity and did not cross-react with stromal cells and only rarely with epithelial cells. CK14 has the added ability to distinguish between florid epithelial hyperplasia involving papilloma and DCIS involving papillomas. CK14 and p63 may be used as an adjunct in assessing difficult papillary lesions of the breast.

Myoepithelial cells in solid variant of intraductal papillary carcinoma of the breast: a potential diagnostic pitfall and a proposal of an immunohistochemical panel in the differential diagnosis with intraductal papilloma with usual ductal hyperplasia.

We examined myoepithelial status in intraductal papillary carcinoma (IPC) along with the expression of high-molecular weight cytokeratin (HMWK) and neuroendocrine markers, with special reference to the differential diagnosis of solid intraductal papillary carcinoma(SIPC) and intraductal papilloma with usual ductal hyperplasia (IP-UDH). Twenty-six (93%) of the twenty-eight intraductal papillomas (IP) had myoepithelial cells in >70% of the epithelial-stromal interface of the intraluminal proliferating component. Six (29%) of twenty-one SIPC had almost complete myoepithelial layer like IP-UDH at the epithelial-stromal interface. HMWK (34 beta E-12) was diffusely positive in 14 (93%) of 15 IP-UDH, but 16 (76%) of 21 SIPC were completely negative for HMWK. Neuroendocrine markers were positive in 14 (67%) of SIPC, but all 28 IPs were completely negative. If only the presence of myoepithelial cells is emphasized as a benign hallmark, about 30% of SIPCs may be underdiagnosed as IP-UDH. However, by using a combination of myoepithelial markers, HMWK, and neuroendocrine markers, all of the 36 solid intraductal papillary lesions were properly classified as benign and malignant. Solid intraductal papillary lesions meeting at least two of the following criteria are highly likely to be malignant: (1) absence of myoepithelial cells(<10% of epithelial-stromal interface of intraluminal proliferating component), (2) negative HMWK(<10%), (3) positive neuroendocrine markers (>10%).

Immunohistochemical staining of papillary breast lesions.

The separation of ductal papilloma from intraductal papillary carcinoma of the breast on hematoxylin and eosin stained sections often presents diagnostic difficulty. Immunohistochemical staining is often employed in diagnosis, historically with smooth muscle actin (SMA). In this study, the staining characteristics of a panel of myoepithelial markers (calponin, p63, P-cadherin), were compared with SMA, and the epithelial expression of CD44s was assessed in 99 papillary lesions. SMA, calponin, and p63 demonstrated myoepithelial cells in 61%, 63%, and 65% of papillary lesions, respectively. However, specificity was quite variable. Calponin-stained stromal myofibroblasts (35% of cases), vessel pericytes (92%), and endothelial cells (69%), though each to a lesser degree than SMA. Calponin also showed cross reactivity with epithelium in 18% of cases. p63 was almost completely restricted to myoepithelial cell nuclei, and did not stain vascular smooth muscle or myofibroblasts. However, p63 stained the epithelial component in one papillary carcinoma, a basal layer of cells in 1 biphasic invasive carcinoma, and the cytoplasm in 1 case. P-cadherin stained both epithelial and myoepithelial cells. The epithelial expression of CD44s and did not distinguish papillomas from papillary carcinomas. Thus, P-cadherin and CD44s are not useful in the characterization of papillary lesions. Given increased specificity as compared with SMA, the combination of p63 and calponin is recommended for analysis of breast papillary lesions.

Expression of androgen receptors and inhibin/activin alpha and betaA subunits in breast apocrine lesions.

The importance of androgens and their receptors inhibin and activin remains unknown for mammary epithelial cells. We investigated the role of these hormones in breast apocrine lesions (BAL) using immunohistochemistry to study androgen receptors (AR) and the inhibin/activin alpha and betaA subunits. Forty-two cases of BAL were evaluated, including 22 cases of fibrocystic disease (FCD) showing prominent apocrine changes, 10 intraductal papillomas with extensive apocrine metaplasia, 5 cases of apocrine carcinoma in situ (CIS), and 5 cases of apocrine carcinoma. Fifty non-apocrine lesions were included as controls: 20 cases of FCD, 5 cases of DCIS, and 25 cases of invasive ductal carcinoma. AR was more frequently expressed in BAL than in non-apocrine lesions (p=0.001). AR expression was not related to tumor progression. AR showed a significant positive correlation with betaA subunits (r=0.832, p<0.001), and an inverse correlation with alpha subunits (r=-0.233). The alpha and betaA subunits demonstrated a significant inverse correlation with each other (r=-0.271, p=0.0048). As the expression of the alpha and betaA subunits reflects inhibin and activin A, respectively, AR and activin A may be implicated in apocrine morphogenesis, but not in tumor progression.

The value of p63 and CK5/6 expression in the differential diagnosis of ductal lesions of breast.

In order to explore the value of p63, smoothmuscle actin (alpha-SMA) and cytokeratin 5/6 (CK5/6) in the differential diagnosis of ductal lesions of breast, 88 tissue specimens of ductal lesions of breast were collected and examined histologically by HE staining. By using immunohistochemistry, the expression of p63, alpha-SMA and CK5/6 was detected. The results showed that in 38 cases of benign breast lesions, the proliferating cells were all positive for p63 and alpha-SMA. In 19 cases of ductal carcinoma in situ (DCIS) and 7 cases of intraductal papillary carcinoma, alpha-SMA positive cells formed a layer of continuous embroider-shaped structure and the p63 positive cells formed a layer of evenly separated embroider-shaped structure around the ducts. There was no cross-reaction between p63 and interstitial myofibroblasts and vascular smooth muscle cells. In 38 cases of benign breast lesions, the positive rate of CK5/6 expression was 100%. In 5 cases of atypical ductal hyperplasia, there were few positive cells in the ducts. In 19 cases of CDIS, no tumor cells expressed CK5/6. In 19 cases of invasive ductal carcinoma, almost no CK5/6 was detectable. It was suggested that p63 could serve as a novel specific marker for the identification of breast myoepithelial cells. CK5/6 is of value in differentiating ductal proliferation of varying degrees, especially in the differentiation between cancerous and non-cancerous changes. Simultaneous detection of p63, CK5/6 and alpha-SMA can help increase the diagnostic accuracy of breast diseases.

Mammary ductoscopy and watchful follow-up substitute microdochectomy in patients with bloody nipple discharge.

PURPOSE: In order to evaluate the diagnostic and therapeutic potential of mammary ductoscopy and watchful follow-up for treating bloody nipple discharge, we investigated the incidence of cancer evolving from the location related to the affected duct and the disappearance of nipple discharge. PATIENTS AND METHODS: Between April 1998 and March 2008, we assessed 709 lesions among 624 patients without a diagnosis of malignancy at the time of 6 months after mammary ductoscopy. The median follow-up time was 5.5 years. We reviewed the subjects' charts retrospectively and investigated the dates on which discharge-related cancer was diagnosed and the disappearance of discharge was noted after the initial examination with mammary ductoscopy. RESULTS: The incidence of cancer evolving from the location related to the pathological duct was 11 % (78/709). Nipple discharge disappeared in 480 (85.1 %) of the 564 followed up lesions, with the exception of 78 breast cancers and 67 resected benign lesions. The rate of disappearance for nipple discharge in the cases of intraductal papilloma at the first examination was 82.5 %. In cases in which no obvious lesions were observed on mammary ductoscopy, there was a 90 % probability that the nipple discharge would disappear, and the rate of evolving breast cancer in the cases of atypical papillary lesions at the first examination was significantly higher than that observed in the cases of intraductal papilloma, at 50 and 8.9 %, respectively. CONCLUSIONS: Information revealed by mammary ductoscopy is useful for differentiating patients who should be subjected to intensive examinations and those who should expect disappearance of their discharge. Mammary ductoscopy and watchful follow-up can substitute microdochectomy in patients with bloody nipple discharge.

Papillary Lesions of the Breast: An Update.

CONTEXT: -Papillary lesions of the breast, characterized by the presence of arborescent fibrovascular cores that support epithelial proliferation, constitute a heterogeneous group of neoplasms with overlapping clinical manifestation and histomorphologic features, but may have divergent biological behavior. These lesions are exclusively intraductal neoplasms, although an invasive carcinoma may rarely have a predominantly papillary architecture. Although recognition of a papillary architecture is typically not challenging, the histologic distinction of these entities is not always straightforward. Historically, different terminologies and variable criteria have been proposed for a given entity by various authorities. The difficulty in classifying these lesions has been further confounded by the scarcity of data and the heterogeneity across different studies with regard to the molecular genetic characteristics of this group of lesions. OBJECTIVE: -To provide an overview focusing on the current concepts in the diagnosis and classification of papillary lesions of the breast incorporating recent molecular genetic advances. DATA SOURCES: -Data were obtained from pertinent peer-reviewed English-language literature. CONCLUSIONS: -The recent evolution of molecular techniques has enhanced our knowledge of the pathogenesis of papillary carcinomas of the breast. This, along with emerging outcome studies, has led to prognosis-based reclassification of some of these entities. Additional studies focusing on the molecular signatures are needed to identify potential decision tools to further stratify these lesions with respect to prognostic significance.

Morphogenesis of the papillary lesions of the breast: phenotypic observation.

Papillary lesions of the breast are a heterogeneous group of diseases characterised by the presence epithelial proliferation supported by fibrovascular stalks. Normal breast tissue does not show papillary morphology and the mechanisms underlying papillary morphogenesis in breast tumours remain poorly understood. Current clinical evidence indicates an indolent behaviour of malignant papillary breast tumours. Herein, we present some phenotypic features that may explain the development of papillary morphology of breast lesions. Active papillary morphogenesis, which appears to reflect a unique mechanism involving interaction between epithelial and mesenchymal elements, is best appreciated in intraductal papilloma and papillary carcinoma. Morphological evidence suggests papillary morphogenesis during oncogenesis is a dynamic process with variable degrees of papillary differentiation among the same lesion and between primary and metastatic tumours. Secondary papillary-like architecture of non-papillary breast lesions exists. Further studies of the molecular mechanisms underlying papillary morphogenesis in the breast and its association with a better outcome are warranted.