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1.  CD44s is useful in the differentiation of benign and malignant papillary lesions of the breast 
Journal of Clinical Pathology  2005;58(11):1185-1188.
Background/Aims: CD44s, the standard form of CD44, has been shown to be downregulated during malignant transformation of breast cancers. It has also been reported recently to be a useful marker in differentiating between benign and malignant papillary lesions of the breast, with high expression in the former. CD44s expression in benign and malignant papillary lesions was evaluated.
Methods: CD44s expression was assessed by immunohistochemistry in 101 benign papillomas and 59 papillary carcinomas (seven invasive papillary carcinomas, 41 papillary ductal carcinomas in situ, and 11 ductal carcinomas involving papillomas).
Results: Patients’ age and tumour size were significantly different between the papilloma and papillary carcinoma groups (p < 0.0001). CD44s showed positive staining in 45 papillomas (45%) and five papillary carcinomas (8%), and the difference was significant (p < 0.0001). The myoepithelial cells, when present, were also positive for CD44s in both groups, with no observable differences. Using CD44s positive staining to differentiate between benign and malignant papillary lesions gives a sensitivity, specificity, and accuracy of 45%, 92%, and 62%, respectively.
Conclusions: CD44s may be useful as an adjunct in the evaluation of morphologically problematic cases of papillary lesion of the breast.
doi:10.1136/jcp.2005.026906
PMCID: PMC1770758  PMID: 16254109
CD44; breast; papillary carcinoma; papilloma
2.  Low-Grade Salivary Duct Carcinoma or Low-Grade Intraductal Carcinoma? Review of the Literature 
Head and Neck Pathology  2013;7(Suppl 1):59-67.
Low-grade salivary duct carcinoma (LG-SDC) is a rare neoplasm characterized by predominant intraductal growth, luminal ductal phenotype, bland microscopic features, and favorable clinical behavior with an appearance reminiscent of florid to atypical ductal hyperplasia to low grade intraductal breast carcinoma. LG-SDC is composed of multiple cysts, cribriform architecture with “Roman Bridges”, “pseudocribriform” proliferations with floppy fenestrations or irregular slits, micropapillae with epithelial tufts, fibrovascular cores, and solid areas. Most of the tumor cells are small to medium sized with pale eosinophilic cytoplasm, and round to oval nuclei, which may contain finely dispersed or dark condensed chromatin. Foci of intermediate to high grade atypia, and invasive carcinoma or micro-invasion have been reported in up to 23 % of cases. The neoplastic cells have a ductal phenotype with coexpression of keratins and S100 protein and are surrounded by a layer of myoepithelial cells in non-invasive cases. The main differential diagnosis of LG-SDC includes cystadenoma, cystadenocarcinoma, sclerosing polycystic adenosis, salivary duct carcinoma in situ/high-grade intraductal carcinoma, and papillary-cystic variant of acinic cell carcinoma. There is no published data supporting the continuous classification of LG-SDC as a variant of cystadenocarcinoma. Given that most LG-SDC are non-invasive neoplasms; the terms “cribriform cystadenocarcinoma” and LG-SDC should be replaced by “low-grade intraductal carcinoma” (LG-IDC) of salivary gland or “low-grade intraductal carcinoma with areas of invasive carcinoma” in those cases with evidence of invasive carcinoma.
doi:10.1007/s12105-013-0460-1
PMCID: PMC3712095  PMID: 23821212
Low-grade salivary duct carcinoma; Low-grade intraductal carcinoma; Cribriform cystadenocarcinoma; Salivary duct carcinoma; Parotid gland; Salivary glands
3.  The role of immunohistochemistry for smooth‐muscle actin, p63, CD10 and cytokeratin 14 in the differential diagnosis of papillary lesions of the breast 
Journal of Clinical Pathology  2006;60(3):315-320.
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.
doi:10.1136/jcp.2006.036830
PMCID: PMC1860581  PMID: 16698948
4.  Intracystic papillary breast cancer: a clinical update 
ecancermedicalscience  2013;7:286.
Introduction:
Intracystic (encysted) papillary cancer (IPC) is a rare entity of breast cancer accounting for approximately (1–2%) of all breast tumours [1], usually presenting in postmenopausal women and having an elusive natural history. The prediction of the biological behaviour of this rare form of breast cancer and the clinical outcome showed its overall favourable prognosis; however, its consideration as a form of ductal carcinoma in situ with non-invasive nature is to be reconsidered as it has been shown to present histologically with invasion of basement membrane and even metastasis [2]. The objective of this review is to shed some light on this rare, diagnostically challenging form of breast cancer, including its radiological, histological, and molecular characteristics and its pathological classification. The final goal is to optimize the clinical management including the role of sentinel lymph node biopsy (SLNB), general management with adjuvant radiotherapy (RT), mammary ductoscopy, and hormonal treatment.
Methods:
A literature review, facilitated by Medline, PubMed, and the Cochrane database, was carried out using the terms ‘Intracystic (encysted) papillary breast cancer’.
Results:
Intracystic papillary breast cancer (IPC) is best managed in the context of a multidisciplinary team. Surgical excision of the lump with margins in excess of 2 mm is considered satisfactory. Sentinel lymph node biopsy (SLNB) is recommended as data have shown the possibility of the presence of invasive cancer in the final histology. RT following IPC alone is of uncertain significance as this form of cancer is usually low grade and rarely recurs. However, if it is associated with DCIS or invasive cancer and found in young women, radiotherapy may be prudent to reduce local recurrence. Large tumours, centrally located or in cases where breast conserving surgery is unable to achieve a favourable aesthetic result, a skin sparing mastectomy with the opportunity for immediate reconstruction can be offered. Adjuvant endocrine therapy may be suggested as almost certainly these tumours are hormonal positive.
Conclusion:
Further research is required to determine the role of adjuvant radiotherapy and endocrine therapy in IPC. Understanding the low-grade nature of this form of breast cancer allows treatment options to be less radical and safely omitted.
doi:10.3332/ecancer.2013.286
PMCID: PMC3539854  PMID: 23304242
intracystic papillary breast cancer; wide local excision; ductal carcinoma in situ; mammary ductoscopy; sentinel lymph node biopsy; radiotherapy; endocrine therapy; local recurrence
5.  Histopathologic risk factors in oral and oropharyngeal squamous cell carcinoma variants: An update with special reference to HPV-related carcinomas 
Accurate identification of the microscopic risk factors of oral and oropharyngeal (OP) squamous cell carcinomas (SCC) and their morphologic variants is of at most importance, as these generally determine treatment modalities, prognosis and overall patient outcome. The great majority of oral and oropharyngeal squamous cell carcinomas are microscopically described as kerartinizing squamous cell carcinoma (KSCC). They bear certain resemblance to keratinizing stratified squamous epithelium. Tobacco habits and excessive consumption of alcoholic beverages have been considered to be the main etiologic agents in these carcinomas. The tumors occurred in older patients more commonly affected the oral tongue and floor of the mouth with well established morphologic risk factors including tumor grade, pattern of invasion and perineural involvement. Within the last 30 years however, the advent and expanding prevalence of high risk human papillomavirus (HPV) as an important etiologic agent for head and neck squamous cell carcinoma, particularly in the OP, has resulted in a significant change in the established morphologic criteria for risk assessment. The majority of HPV relate carcinomas of the OP are nonkeratinizing squamous cell carcinoma (NKSCC). These tumors are found to be more responsive to treatment with a favorable patient outcome and good prognosis. Consequently, alterations in treatment protocols aimed at de-escalation are currently being evaluated. More recently, other morphologic variants that are HPV positive are reported with increasing frequency in the OP and other head and neck sites. As a result, several clinical and pathologic questions have emerged. Importantly, whether the virus is biologically active in these tumors and involved in their pathogenesis, and second, what are the clinical implications with regard to patient management and outcome in the HPV-related variants. Examples of HPV-related squamous cell carcinoma variants that will be addressed here are: basaloid squamous cell carcinoma (BSCC), undifferentiated carcinoma (UCa), papillary squamous carcinoma (PSCC) and small cell carcinoma. Some studies have suggested favorable prognosis in some variants, analogous to that of the (NKSCC), while others showed poorer outcome. So far the number of studies on this subject is limited and the number of cases evaluated in each investigation is few. Because of that, it is prudent at this stage, not to alter management protocols as a result of identification of HPV in these variants and to await additional information
Key words:Histopathologic risk-factors, oral cavity, oropharynx, squamous cell carcinoma variants, keratinizing squamous cell carcinoma, nonkeratinizing squamous cell carcinoma, HPV, basaloid squamous cell carcinoma, undifferentiated carcinoma, papillary squamous cell carcinoma, small cell carcinoma.
doi:10.4317/medoral.20184
PMCID: PMC4119314  PMID: 24880454
6.  Predictors of recurrence in breast cancer subtypes with negative lymph node in a Chinese population 
To establish a series of objective parameters to predict the risk of relapse from axillary lymph node-negative (ANN) breast cancer, and evaluate the patterns of recurrence according to molecular subtypes, we collected information on 2126 consecutive breast cancer patients operated between 2002 and 2006. In this case-control study, 212 patients experiencing recurrence or breast cancer related death were defined as ‘poor group’. Another 212 patients were selected from the remaining cases with stratified sampling method to comprise the ‘good group’. Significant differences were found in vascular invasion, grade and molecular subtype between the two groups. Expression of ER and PR in the ‘poor group’ was lower (P < 0.05). However, positive rates of Ki67, p53 and VEGF in the ‘poor group’ were higher (P < 0.05). Multivariate analysis revealed that molecular subtype, expression of VEGF, tumor grade, and vascular invasion were closely correlated with bad outcome. Analysis of the ‘poor group’ demonstrated that ‘HER2 positive’ and ‘triple negative’ subtypes more commonly suffered from distant metastases and death. No metastasis was found in patients with pure invasive papillary carcinoma, invasive cribriform carcinoma or adenoid cystic carcinoma, whereas the diagnoses of invasive micropapillary carcinoma, invasive apocrine carcinoma, invasive papillary carcinoma mixed with invasive ductal carcinoma, or metaplastic carcinoma were correlated with distant metastasis and death. In conclusion, molecular subtype and expression of VEGF are useful markers for predicting prognosis of ANN breast cancer patients. ‘Luminal A-like’ subtype has better outcome than others. Moreover, molecular subtypes have different recurrence patterns.
PMCID: PMC4097226  PMID: 25031741
Breast cancer; molecular subtype; p53; VEGF; recurrence
7.  DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer 
PLoS Medicine  2009;6(5):e1000068.
Ann Killary and colleagues describe a new gene that is genetically altered in breast tumors, and that may provide a new breast cancer prognostic marker.
Background
Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium–associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.
Methods and Findings
Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER−, PR−, HER-2−) of breast cancers with poor prognosis.
Conclusions
Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease.
Editors' Summary
Background
Each year, more than one million women discover that they have breast cancer. This type of cancer begins when cells in the breast that line the milk-producing glands or the tubes that take the milk to the nipples (glandular and ductal epithelial cells, respectively) acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The uncontrolled division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy or chemotherapy. These “adjuvant” therapies are designed to kill any remaining cancer cells but can make patients very ill. Generally speaking, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Although breast cancer is usually diagnosed in women in their 50s or 60s, some women develop breast cancer much earlier. In these women, the disease is often very aggressive. Compared to older women, young women with breast cancer have a lower overall survival rate and their cancer is more likely to recur locally or to metastasize. It would be useful to be able to recognize those younger women at the greatest risk of cancer recurrence so that they could be offered intensive surveillance and adjuvant therapy; those women at a lower risk could have gentler treatments. To achieve this type of “stratification,” the genetic changes that underlie breast cancer in young women need to be identified. In this study, the researchers discover a gene that is genetically altered (by mutations or deletion) in early-onset breast cancer and then investigate whether its expression can predict outcomes in women with this disease.
What Did the Researchers Do and Find?
The researchers used “suppression subtractive hybridization” to identify a new gene in a region of human Chromosome 1 where loss of heterozygosity (LOH; a genetic alteration associated with cancer development) frequently occurs. They called the gene DEAR1 (ductal epithelium-associated RING Chromosome 1) to indicate that it is expressed in ductal and glandular epithelial cells and encodes a “RING finger” protein (specifically, a subtype called a TRIM protein; RING finger proteins such as BRCA1 and BRCA2 have been implicated in early cancer development and in a large fraction of inherited breast cancers). DEAR1 expression was reduced or lost in several ductal carcinomas in situ (a local abnormality that can develop into breast cancer) and advanced breast cancers, the researchers report. Furthermore, many breast tumors carried DEAR1 missense mutations (genetic changes that interfere with the normal function of the DEAR1 protein) or had lost both copies of DEAR1 (the human genome contains two copies of most genes). To determine the function of DEAR1, the researchers replaced a normal copy of DEAR1 into a breast cancer cell that had a mutation in DEAR1. They then examined the growth of these genetically manipulated cells in special three-dimensional cultures. The breast cancer cells without DEAR1 grew rapidly without an organized structure while the breast cancer cells containing the introduced copy of DEAR1 formed structures that resembled normal breast acini (sac-like structures that secrete milk). In normal human mammary epithelial cells, the researchers silenced DEAR1 expression and also showed that without DEAR1, the normal mammary cells lost their ability to form proper acini. Finally, the researchers report that DEAR1 expression (detected “immunohistochemically”) was frequently lost in women who had had early-onset breast cancer and that the loss of DEAR1 expression correlated with reduced local recurrence-free survival, a strong family history of breast cancer and with a breast cancer subtype that has a poor outcome.
What Do These Findings Mean?
These findings indicate that genetic alteration and loss of expression of DEAR1 are common in breast cancer. Although laboratory experiments may not necessarily reflect what happens in people, the results from the three-dimensional culture of breast epithelial cells suggest that DEAR1 may regulate the normal acinar structure of the breast. Consequently, loss of DEAR1 expression could be an early event in breast cancer development. Most importantly, the correlation between DEAR1 expression and both local recurrence in early-onset breast cancer and a breast cancer subtype with a poor outcome suggests that it might be possible to use DEAR1 expression to identify women with early-onset breast cancer who have an increased risk of local recurrence so that they get the most appropriate treatment for their cancer.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000068.
This study is further discussed in a PLoS Medicine Perspective by Senthil Muthuswamy
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on genetic alterations in breast cancer (in English and Spanish)
The MedlinePlus Encyclopedia provides information for patients about breast cancer; MedlinePlus also provides links to many other breast cancer resources (in English and Spanish)
The UK charities Cancerbackup (now merged with MacMillan Cancer Support) and Cancer Research UK also provide detailed information about breast cancer
doi:10.1371/journal.pmed.1000068
PMCID: PMC2673042  PMID: 19536326
8.  Unusual case of insitu (intracystic) papillary carcinoma of breast 
The term “intracystic papillary ductal carcinoma in situ”, has recently changed and is now more appropriately referred to as “intracystic papillary carcinoma’’ constituting only 0.5% to 1% of all breast cancers. Herein, we discuss an unusual case of intracystic insitu papillary carcinoma of breast in a postmenopausal woman, the diagnosis of which was made on histopathology and confirmed by immunohistochemistry. Patient responded well to postoperative adjuvant radiotherapy without any recurrence, thereby preventing further morbidity and mortality related to invasion or tumor progression. So careful histopathological evaluation is the mainstay to arrive at the correct diagnosis to avoid untoward complications related to under diagnosis and /over diagnosis.
doi:10.12998/wjcc.v1.i7.227
PMCID: PMC3856298  PMID: 24340273
Insitu papillary carcinoma; Histopathology
9.  Intracystic papillary carcinoma of the breast in a 21-year old premenopausal Nigerian woman: a case report 
Rare Tumors  2009;1(2):e50.
We report the case of a 21-year-old Nigerian woman who presented to us with features of intracystic papillary carcinoma, a rare form of breast cancer usually seen in postmenopausal women in their sixth to eighth decades of life. To the best of our knowledge, there has been only one other case report of this lesion occurring in women in their second decade of life.
Physical examination showed a well-defined mass, 54 mm in diameter, in the upper proximal quadrant of the right breast close to the areola, histologically composed of monotypic epithelial cells disposed in solid, cystic, and papillary patterns. A diagnosis of intracystic papillary carcinoma was made because of the presence of intracystic arborization of the fibrovascular stroma, a monotonous cell population, the presence of mitoses, and the lack of myoepithelial cells determined by immunohistochemistry using calponin and p63 stains. Estrogen receptor status was positive while progesterone status and HER-2-neu receptor status were negative.
The patient has survived for 12 months without any sign of recurrence after the last surgical resection of the tumor.
doi:10.4081/rt.2009.e50
PMCID: PMC2994473  PMID: 21139929
intracystic papillary carcinoma; breast; young women.
10.  Paget’s disease of the breast: clinical, imaging and pathologic findings: a review of 16 patients 
Objectives:
To determine the clinical, imaging and pathological findings of Paget’s disease of the breast.
Materials and methods:
Approval by Institutional Review Board was granted and informed consent was waived. Retrospective review of the pathological diagnosis of 2,361 women with breast carcinoma between January 2004 and April 2010 revealed 27 patients with Paget’s disease of the breast. The clinical, mammographic and ultrasonographic images were retrospectively reviewed.
Results:
The prevalence of Paget’s disease of the breast was 1.14% of all breast carcinoma at this institution. Of the 27 patients with Paget’s disease, only 16 had imaging studies and this group constituted the basis of this study. All 16 patients were women, with ages ranging from 36–68 years (mean age 50.31 years). Eleven patients presented with clinical findings suggestive of Paget’s disease of the breast. Seven of these 11 patients also had associated palpable mass(es). Four patients presented with a palpable mass alone and one presented with bloody nipple discharge alone. Mammography was performed in all 16 patients and ultrasonography (US) in 15 patients. Of the 16 mammographic studies, two were negative. Of the 15 US studies, three were negative. Of these three negative US studies, two also had negative mammography and one had pleomorphic microcalcifications on mammogram. US was helpful in detecting multifocality in two patients. Mammography was 100% positive in patients who presented with palpable breast mass(es) and bloody nipple discharge, but 50% positive in patients who had clinically suggestive Paget’s disease alone. Almost all patients (15/16) had underlying breast malignancies. Seven patients had multifocality or multicentricity. Modified radical mastectomy was performed in 13 patients, simple mastectomy in two, and wide local excision in one patient. Pathological findings were ductal carcinoma in situ (DCIS) (n = 3), invasive ductal carcinoma (IDC) (n = 10), metaplastic carcinoma (n = 1), invasive lobular carcinoma (ILC) (n = 1), and only Paget’s disease of the nipple without underlying breast carcinoma (n = 1).
Conclusion:
Patients with Paget’s disease of the breast have a high incidence of an underlying breast carcinoma. Most of the patients in this study presented late and were more likely to have positive mammograms. Mammography should be performed to identify the underlying breast carcinoma. Those who have only nipple areolar changes and no palpable mass have less positive mammography and less invasive carcinoma.
doi:10.2349/biij.7.2.e16
PMCID: PMC3265154  PMID: 22287988
Coronary artery disease; single photon emission computed tomography; positron emission tomography; computed tomography; diagnostic value
11.  Cancer Screening with Digital Mammography for Women at Average Risk for Breast Cancer, Magnetic Resonance Imaging (MRI) for Women at High Risk 
Executive Summary
Objective
The purpose of this review is to determine the effectiveness of 2 separate modalities, digital mammography (DM) and magnetic resonance imaging (MRI), relative to film mammography (FM), in the screening of women asymptomatic for breast cancer. A third analysis assesses the effectiveness and safety of the combination of MRI plus mammography (MRI plus FM) in screening of women at high risk. An economic analysis was also conducted.
Research Questions
How does the sensitivity and specificity of DM compare to FM?
How does the sensitivity and specificity of MRI compare to FM?
How do the recall rates compare among these screening modalities, and what effect might this have on radiation exposure? What are the risks associated with radiation exposure?
How does the sensitivity and specificity of the combination of MRI plus FM compare to either MRI or FM alone?
What are the economic considerations?
Clinical Need
The effectiveness of FM with respect to breast cancer mortality in the screening of asymptomatic average- risk women over the age of 50 has been established. However, based on a Medical Advisory Secretariat review completed in March 2006, screening is not recommended for women between the ages of 40 and 49 years. Guidelines published by the Canadian Task Force on Preventive Care recommend mammography screening every 1 to 2 years for women aged 50 years and over, hence, the inclusion of such women in organized breast cancer screening programs. In addition to the uncertainty of the effectiveness of mammography screening from the age of 40 years, there is concern over the risks associated with mammographic screening for the 10 years between the ages of 40 and 49 years.
The lack of effectiveness of mammography screening starting at the age of 40 years (with respect to breast cancer mortality) is based on the assumption that the ability to detect cancer decreases with increased breast tissue density. As breast density is highest in the premenopausal years (approximately 23% of postmenopausal and 53% of premenopausal women having at least 50% of the breast occupied by high density), mammography screening is not promoted in Canada nor in many other countries for women under the age of 50 at average risk for breast cancer. It is important to note, however, that screening of premenopausal women (i.e., younger than 50 years of age) at high risk for breast cancer by virtue of a family history of cancer or a known genetic predisposition (e.g., having tested positive for the breast cancer genes BRCA1 and/or BRCA2) is appropriate. Thus, this review will assess the effectiveness of breast cancer screening with modalities other than film mammography, specifically DM and MRI, for both pre/perimenopausal and postmenopausal age groups.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined whereas mortality is decreasing, though at a slower rate. The observed decreases in mortality rates may be attributable to screening, in addition to advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the Surveillance, Epidemiology and End Results (better known as SEER) cancer registry in the United States, indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20 year period, from 2.7 to 25 per 100,000.
There is a 4-fold lower incidence of breast cancer in the 40 to 49 year age group than in the 50 to 69 year age group (approximately 140 per 100,000 versus 500 per 100,000 women, respectively). The sensitivity of FM is also lower among younger women (approximately 75%) than for women aged over 50 years (approximately 85%). Specificity is approximately 80% for younger women versus 90% for women over 50 years. The increased density of breast tissue in younger women is likely responsible for the decreased accuracy of FM.
Treatment options for breast cancer vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy and/or radiotherapy. Surgery is the first-line intervention for biopsy-confirmed tumors. The subsequent use of radiation, chemotherapy or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is considered a noninvasive tumour.
Women at high risk for breast cancer are defined as genetic carriers of the more commonly known breast cancer genes (BRCA1, BRCA2 TP53), first degree relatives of carriers, women with varying degrees of high risk family histories, and/or women with greater than 20% lifetime risk for breast cancer based on existing risk models. Genetic carriers for this disease, primarily women with BRCA1 or BRCA2 mutations, have a lifetime probability of approximately 85% of developing breast cancer. Preventive options for these women include surgical interventions such as prophylactic mastectomy and/or oophorectomy, i.e., removal of the breasts and/or ovaries. Therefore, it is important to evaluate the benefits and risks of different screening modalities, to identify additional options for these women.
This Medical Advisory Secretariat review is the second of 2 parts on breast cancer screening, and concentrates on the evaluation of both DM and MRI relative to FM, the standard of care. Part I of this review (March 2006) addressed the effectiveness of screening mammography in 40 to 49 year old average-risk women. The overall objective of the present review is to determine the optimal screening modality based on the evidence.
Evidence Review Strategy
The Medical Advisory Secretariat followed its standard procedures and searched the following electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database. The subject headings and keywords searched included breast cancer, breast neoplasms, mass screening, digital mammography, magnetic resonance imaging. The detailed search strategies can be viewed in Appendix 1.
Included in this review are articles specific to screening and do not include evidence on diagnostic mammography. The search was further restricted to English-language articles published between January 1996 and April 2006. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters.
Digital Mammography: In total, 224 articles specific to DM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 5 health technology assessments (HTAs) (plus 1 update) and 4 articles specific to screening with DM.
Magnetic Resonance Imaging: In total, 193 articles specific to MRI were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 HTAs and 7 articles specific to screening with MRI.
The evaluation of the addition of FM to MRI in the screening of women at high risk for breast cancer was also conducted within the context of standard search procedures of the Medical Advisory Secretariat. as outlined above. The subject headings and keywords searched included the concepts of breast cancer, magnetic resonance imaging, mass screening, and high risk/predisposition to breast cancer. The search was further restricted to English-language articles published between September 2007 and January 15, 2010. Case reports, comments, editorials, nonsystematic reviews, and letters were not excluded.
MRI plus mammography: In total, 243 articles specific to MRI plus FM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 previous HTAs, and 1 systematic review of 11 paired design studies.
Inclusion Criteria
English-language articles, and English or French-language HTAs published from January 1996 to April 2006, inclusive.
Articles specific to screening of women with no personal history of breast cancer.
Studies in which DM or MRI were compared with FM, and where the specific outcomes of interest were reported.
Randomized controlled trials (RCTs) or paired studies only for assessment of DM.
Prospective, paired studies only for assessment of MRI.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which women had been previously diagnosed with breast cancer.
Studies in which the intervention (DM or MRI) was not compared with FM.
Studies assessing DM with a sample size of less than 500.
Intervention
Digital mammography.
Magnetic resonance imaging.
Comparator
Screening with film mammography.
Outcomes of Interest
Breast cancer mortality (although no studies were found with such long follow-up).
Sensitivity.
Specificity.
Recall rates.
Summary of Findings
Digital Mammography
There is moderate quality evidence that DM is significantly more sensitive than FM in the screening of asymptomatic women aged less than 50 years, those who are premenopausal or perimenopausal, and those with heterogeneously or extremely dense breast tissue (regardless of age).
It is not known what effect these differences in sensitivity will have on the more important effectiveness outcome measure of breast cancer mortality, as there was no evidence of such an assessment.
Other factors have been set out to promote DM, for example, issues of recall rates and reading and examination times. Our analysis did not show that recall rates were necessarily improved in DM, though examination times were lower than for FM. Other factors including storage and retrieval of screens were not the subject of this analysis.
Magnetic Resonance Imaging
There is moderate quality evidence that the sensitivity of MRI is significantly higher than that of FM in the screening of women at high risk for breast cancer based on genetic or familial factors, regardless of age.
Radiation Risk Review
Cancer Care Ontario conducted a review of the evidence on radiation risk in screening with mammography women at high risk for breast cancer. From this review of recent literature and risk assessment that considered the potential impact of screening mammography in cohorts of women who start screening at an earlier age or who are at increased risk of developing breast cancer due to genetic susceptibility, the following conclusions can be drawn:
For women over 50 years of age, the benefits of mammography greatly outweigh the risk of radiation-induced breast cancer irrespective of the level of a woman’s inherent breast cancer risk.
Annual mammography for women aged 30 – 39 years who carry a breast cancer susceptibility gene or who have a strong family breast cancer history (defined as a first degree relative diagnosed in their thirties) has a favourable benefit:risk ratio. Mammography is estimated to detect 16 to 18 breast cancer cases for every one induced by radiation (Table 1). Initiation of screening at age 35 for this same group would increase the benefit:risk ratio to an even more favourable level of 34-50 cases detected for each one potentially induced.
Mammography for women under 30 years of age has an unfavourable benefit:risk ratio due to the challenges of detecting cancer in younger breasts, the aggressiveness of cancers at this age, the potential for radiation susceptibility at younger ages and a greater cumulative radiation exposure.
Mammography when used in combination with MRI for women who carry a strong breast cancer susceptibility (e.g., BRCA1/2 carriers), which if begun at age 35 and continued for 35 years, may confer greatly improved benefit:risk ratios which were estimated to be about 220 to one.
While there is considerable uncertainty in the risk of radiation-induced breast cancer, the risk expressed in published studies is almost certainly conservative as the radiation dose absorbed by women receiving mammography recently has been substantially reduced by newer technology.
A CCO update of the mammography radiation risk literature for 2008 and 2009 gave rise to one article by Barrington de Gonzales et al. published in 2009 (Barrington de Gonzales et al., 2009, JNCI, vol. 101: 205-209). This article focuses on estimating the risk of radiation-induced breast cancer for mammographic screening of young women at high risk for breast cancer (with BRCA gene mutations). Based on an assumption of a 15% to 25% or less reduction in mortality from mammography in these high risk women, the authors conclude that such a reduction is not substantially greater than the risk of radiation-induced breast cancer mortality when screening before the age of 34 years. That is, there would be no net benefit from annual mammographic screening of BRCA mutation carriers at ages 25-29 years; the net benefit would be zero or small if screening occurs in 30-34 year olds, and there would be some net benefit at age 35 years or older.
The Addition of Mammography to Magnetic Resonance Imaging
The effects of the addition of FM to MRI screening of high risk women was also assessed, with inclusion and exclusion criteria as follows:
Inclusion Criteria
English-language articles and English or French-language HTAs published from September 2007 to January 15, 2010.
Articles specific to screening of women at high risk for breast cancer, regardless of the definition of high risk.
Studies in which accuracy data for the combination of MRI plus FM are available to be compared to that of MRI and FM alone.
RCTs or prospective, paired studies only.
Studies in which women were previously diagnosed with breast cancer were also included.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which there was insufficient data on the accuracy of MRI plus FM.
Intervention
Both MRI and FM.
Comparators
Screening with MRI alone and FM alone.
Outcomes of Interest
Sensitivity.
Specificity.
Summary of Findings
Magnetic Resonance Imaging Plus Mammography
Moderate GRADE Level Evidence that the sensitivity of MRI plus mammography is significantly higher than that of MRI or FM alone, although the specificity remains either unchanged or decreases in the screening of women at high risk for breast cancer based on genetic/familial factors, regardless of age.
These studies include women at high risk defined as BRCA1/2 or TP53 carriers, first degree relatives of carriers, women with varying degrees of high risk family histories, and/or >20% lifetime risk based on existing risk models. This definition of high risk accounts for approximately 2% of the female adult population in Ontario.
PMCID: PMC3377503  PMID: 23074406
12.  Multiple genes are hypermethylated in intraductal papillary mucinous neoplasms of the pancreas 
Ductal adenocarcinoma of the pancreas is the fourth leading cause of cancer death and is usually diagnosed late. Intraductal papillary mucinous neoplasms are an increasingly recognized precursor to invasive ductal adenocarcinoma of the pancreas. Identifying the alterations in DNA methylation that arise during intraductal papillary mucinous neoplasm development may facilitate the development of markers that could be used to differentiate intraductal papillary mucinous neoplasms from non-neoplastic pancreatic cystic lesions. Surgically resected intraductal papillary mucinous neoplasms and adjacent ductal adenocarcinomas were microdissected from 50 patients. Normal pancreas was also obtained from 27 patients with intraductal papillary mucinous neoplasms or pancreatic adenocarcinomas and 10 patients with well-differentiated pancreatic endocrine neoplasms. Methylation-specific PCR was performed on isolated DNA for seven genes (SPARC, SARP2, TSLC1, RELN, TFPI2, CLDN5, UCHL1) known to be commonly aberrantly methylated in pancreatic ductal adenocarcinomas. The mean percentage of genes methylated in invasive ductal adenocarcinomas arising in association with an intraductal papillary mucinous neoplasm (mean±s.d., 81±17%) was significantly higher than that in noninvasive-intraductal papillary mucinous neoplasms (57±26%, P=0.007) or peritumoral normal epithelial cells (22±17%, P<0.0001). Carcinomas (intraductal papillary mucinous neoplasms with carcinoma in situ or their associated infiltrating adenocarcinoma) had significantly more methylated genes (71±19%) than low-grade (low and moderate dysplasia) intraductal papillary mucinous neoplasms (44±26%, P<0.0001). The mean percentage of genes methylated in histologically normal pancreatic ductal cells from patients with ductal neoplasia (22±17%) was significantly higher than in normal ductal cells from patients with well-differentiated pancreatic endocrine neoplasms (4±7%, P=0.002). Thus, aberrant DNA methylation increases with histologic grades of intraductal papillary mucinous neoplasm. Low-level aberrant methylation in the normal ductal cells is more prevalent in patients with ductal neoplasia than in controls without ductal neoplasms and may contribute to carcinogenesis. The detection of aberrant methylation in pancreatic cystic lesions could facilitate the diagnosis of intraductal papillary mucinous neoplasms.
doi:10.1038/modpathol.2008
PMCID: PMC2678809  PMID: 18820670
intraductal papillary mucinous neoplasm; DNA methylation; pancreatic cancer; SPARC; pancreatic endocrine neoplasm
13.  Urothelial Tumors of the Urinary Bladder in Young Patients: A Clinicopathologic Study of 59 Cases 
Context
Urothelial tumors are rare in young patients. Because of its rarity, the natural history of the disease in young patients remains poorly understood.
Objective
To understand the pathologic and clinical features of urothelial tumors of the urinary bladder in young patients.
Design
We identified 59 young patients with urothelial tumors of the urinary bladder treated at our institution and analyzed the tumors’ pathologic features and the patients’ clinical outcomes.
Results
All patients were 30 years old or younger, with a mean age of 23.5 years (range, 4 to 30). Thirty-eight patients were male, and 21 were female. Most tumors were noninvasive papillary urothelial tumors (n = 49), including papillary urothelial neoplasms of low malignant potential (n = 7), low-grade papillary urothelial carcinomas (n = 38), and high-grade papillary urothelial carcinomas (n = 4). Only a minority of urothelial tumors were invasive, invading the lamina propria (n = 5), muscularis propria (n = 4), or perivesical soft tissue (n = 1). Clinical follow-up information was available for 41 patients, with a mean follow-up time of 77 months. Of 31 patients with noninvasive papillary urothelial tumors, only 1 patient later developed an invasive urothelial carcinoma and died of the disease, and 30 of these patients were alive at the end of follow-up, although 10 had local tumor recurrences. In the 10 patients with invasive urothelial carcinomas, 3 patients died of the disease and 5 others were alive with metastases.
Conclusion
Urothelial tumors in young patients are mostly noninvasive papillary carcinomas and have an excellent prognosis; however, a small subset of patients may present with high-grade invasive urothelial carcinomas that result in poor clinical outcomes.
doi:10.5858/arpa.2012-0322-OA
PMCID: PMC3927706  PMID: 24079760
Papillary urothelial carcinoma; Urinary bladder; Renal pelvis; Young patients
14.  Papillary squamotransitional cell carcinoma of the uterine cervix: A histomorphological and immunohistochemical study of nine cases 
Background:
Papillary squamotransitional cell carcinoma (PSCC) is a distinctive subcategory of squamous cell carcinoma of the uterine cervix. It has a propensity for local recurrence and late metastasis. Histologically, it can be misinterpreted as transitional cell carcinoma, or other papillary lesions of the cervix including squamous papilloma, verrucous carcinoma or cervical intraepithelial neoplasia grade 3 with papillary configuration.
Materials and Methods:
Nine cases of PSCC of the uterine cervix were diagnosed on a cervical biopsy specimen on routine hematoxylin and eosin (H and E) stained sections. Their clinic-morphological features were analyzed. The cases were further evaluated immunohistochemically by cytokeratin 7 (CK7), cytokeratin 20 (CK20), p53 and Ki-67.
Results:
The patients ranged in age from 35 years to 75 years; with abnormal uterine bleeding being the most common clinical presentation. All the cases showed papillary architecture with fibrovascular cores lined by multilayered atypical epithelium. Three cell types were observed: Clear, intermediate and basaloid. Stromal invasion was seen in five cases, whereas in the remaining four cases, the biopsy specimen was too superficial to definitely assess invasion. Immunohistochemically, eight cases were CK7+/CK20– and one case was CK7–/CK20–. All nine cases showed nuclear accumulation of mutant p53. Moderate and high proliferative activity was observed in two and seven cases, respectively. Five of patients for whom follow-up information was available underwent radical hysterectomy and two of them were disease free 18 months following treatment.
Conclusion:
PSCC of the uterine cervix are a clinicomorphologically distinct group of cervical lesions that display a morphologic spectrum. They are potentially aggressive malignant tumors that should be distinguished from transitional cell carcinoma and other papillary lesions of the uterine cervix.
doi:10.4103/0971-5851.116177
PMCID: PMC3764746  PMID: 24049289
Cervix; cytokeratin 7/cytokeratin 20; Ki–67; p53; papillary squamotransitional cell carcinoma
15.  Intracystic Papillary Carcinoma of the Breast in Males: A Case Report and Review of the Literature 
Carcinoma of the male breast is a relatively rare disease that accounts for less than 1% of all the cases of cancer in men. Intracystic Papillary Carcinoma (IPC) is an extremely rare disease of the male breast, with a few case reports. The prognosis is excellent for the patients who are diagnosed with IPC, regardless of whether the tumour is in-situ or of an invasive type. We are reporting the case of a 50 year old man who presented with a painless cystic lump in the left breast. Ultrasonography revealed an intracystic tumour. Fine needle aspiration suggested a papillary tumour. The patient underwent simple mastectomy without a sentinel lymph node biopsy. The final pathologic examination revealed an intracystic papillary carcinoma of a low nuclear grade without an invasion.
doi:10.7860/JCDR/2013/4998.2828
PMCID: PMC3616586  PMID: 23634426
Intracystic papillary carcinoma; Male breast cancer
16.  Sonographically-Guided 14-Gauge Core Needle Biopsy for Papillary Lesions of the Breast 
Korean Journal of Radiology  2007;8(3):206-211.
Objective
We wanted to assess the need for surgical excising papillary lesions of the breast that were diagnosed upon sonographically guided 14-gauge core needle biopsy.
Materials and Methods
Sixty-nine women (age range: 25-74 years, mean age: 51.7 years) with 69 papillary lesions (4.9%) were diagnosed and followed after performing sonographically guided 14-gauge core needle biopsies. Surgical excision was performed for 44 (64%) of 69 papillary lesions, and 25 lesions were followed with imaging studies (range: 6-46 months, mean: 17.9 months). The histologic findings upon core biopsy were compared with the surgical, imaging and follow-up findings.
Results
Core needle biopsies of 69 lesions yielded tissue that was classified as benign for 43 lesions, atypical for 18 lesions and malignant for eight lesions. Of the 43 lesions that yielded benign papilloma upon core needle biopsy, one had intraductal papillary carcinoma found upon surgery. An immediate surgical biopsy was recommended for this lesion because of the imaging-histologic discordance. No additional carcinoma was found during the imaging follow-up. Surgical excision was performed for 17 atypical papillary lesions, and this revealed intraductal (n = 6) or invasive (n = 2) papillary carcinoma in 8 (47%) lesions. Of the seven intraductal papillary carcinomas, surgery revealed invasive papillary carcinoma in one (14%).
Conclusion
Our results suggest that papillary lesions of the breast that are diagnosed as benign upon sonographically guided 14-gauge core needle biopsy can be followed when the results are concordant with the imaging findings.
doi:10.3348/kjr.2007.8.3.206
PMCID: PMC2627411  PMID: 17554187
Breast, biopsy; Breast, US; Breast, neoplasm
17.  Surgical outcomes of borderline breast lesions detected by needle biopsy in a breast screening program 
Background
The Australian Capital Territory and South East New South Wales branch of BreastScreen Australia (BreastScreen ACT&SENSW) performs over 20,000 screening mammograms annually. This study describes the outcome of surgical biopsies of the breast performed as a result of a borderline lesion being identified after screening mammography and subsequent workup.
A secondary aim was to identify any parameters, such as a family history of breast cancer, or radiological findings that may indicate which borderline lesions are likely to be upgraded to malignancy after surgery.
Methods
From a period of just over eight years, all patients of BreastScreen ACT&SENSW who were diagnosed with a borderline breast lesion were identified. These women had undergone needle biopsy in Breastscreen ACT&SENSW and either atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), atypical lobular hyperplasia (ALH), radial scar/complex sclerosing lesion, papillary lesion, mucocoele-like lesion (MLL) or lobular carcinoma in situ (LCIS) was found. Final outcomes for each type of borderline lesion after referral for surgical biopsy were recorded and analysed. Results of the surgical biopsy were compared to the type of needle biopsy and its result, radiological findings and family history status.
Results
Of the 94 surgical biopsies performed due to the presence of a borderline breast lesion, 20% showed benign pathology, 55% remained as borderline lesions, 17% showed non-invasive malignancy and 7% showed invasive malignancy. VALCS biopsy was the most common needle biopsy method used to identify the lesions in this study (76%). Malignant outcomes resulted from 24% of the surgical biopsies, with the most common malignant lesion being non-comedo ductal carcinoma in situ (DCIS). The most common borderline lesion for which women underwent surgical biopsy was ADH (38%). Of these women, 22% were confirmed as ADH on surgical biopsy and 47% with a malignancy.
Conclusions
Further research is required to determine whether characteristics of the mammographic lesion (particularly calcification patterns), the area targeted for biopsy and number of core samples retrieved, can indicate a closer correlation with eventual pathology. This study identified no findings in the diagnostic assessment that could exclude women with borderline lesions from surgical biopsy.
doi:10.1186/1477-7819-8-78
PMCID: PMC2945347  PMID: 20822548
18.  Intracystic papillary carcinoma associated with ductal carcinoma in situ in a male breast: a case report 
Cases Journal  2009;2:7260.
Introduction
Intracystic papillary carcinoma represents a small distinctive subgroup of noninvasive breast cancer, accounts for <0.5% of breast malignancies and is extremely rare in men, it was originally reported as a localized non-invasive carcinoma, but is usually associated with ductal carcinoma in situ around the main tumor or invasive carcinoma.
Case presentation
We report a case of 50-year-old man with intracystic papillary carcinoma in man with ductal carcinoma in situ who underwent a tumorectomy following by a radical Patey intervention (Halsted).
Conclusion
Nowadays, there is still no clear consensus regarding optimal treatment of intracystic papillary carcinoma. Most papers reinforce the importance of an adequate surgical margin in conservative treatment. Surgeons must pay much attention to the potential for ductal carcinoma in situ around the tumor when selecting the operative procedure.
doi:10.4076/1757-1626-2-7260
PMCID: PMC2740303  PMID: 19829939
19.  Follow-up of breast papillary lesion on core needle biopsy: experience in African-American population 
Diagnostic Pathology  2014;9:86.
Background
The optimal course of clinical follow-up after a diagnosis of breast papillary lesion on a core needle biopsy (CNB) remains elusive. In particular, no reports in literature have addressed this question in African-American population. We describe our experience with breast papillary lesions in a primarily African-American population.
Methods
A search of our database for breast papillary lesions diagnosed on CNB between September 2002 and September 2012 was conducted. Cases were categorized into benign, atypical, and malignant. CK5/6 and CK903 stains were performed when necessary.
Results
A total of 64 breast papillary lesions were diagnosed on CNB, including 55 (86%) benign papillary lesions, 6 (9%) atypical lesions, and 3 (5%) intraductal papillary carcinomas. Of these 64 patients, 29 patients (25 African-Americans, 3 Hispanics, 1 Asian American) underwent lumpectomy within 6 months after CNB. Pathology of the lumpectomy showed: five of the 25 (20%) benign papillary lesions on needle biopsy were upgraded to intraductal or invasive papillary carcinoma; 2 of the 3 atypical papillary lesion cases on core biopsy were upgraded (67%), one into intraductal papillary carcinoma, the other invasive papillary carcinoma; the only case of malignant papillary lesion on CNB remained as intraductal papillary carcinoma on lumpectomy. The rate of upgrade in lumpectomy/mastectomy was 25%. CK5/6 and CK903 immunostains were performed on all seven core needle biopsies that were later upgraded.
Conclusions
In our predominantly African-American urban population, 25% of benign or atypical papillary lesions diagnosed on CNB was upgraded in the final excisional examination. Early excision of all papillary lesions diagnosed on CNB may be justified in this patient population.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7950117821177201
doi:10.1186/1746-1596-9-86
PMCID: PMC4039081  PMID: 24762090
Breast papillary lesion; Core needle biopsy; Immunostains; African-Americans
20.  Measurement of tumour size with mammography, sonography and magnetic resonance imaging as compared to histological tumour size in primary breast cancer 
BMC Cancer  2013;13:328.
Background
Tumour size in breast cancer influences therapeutic decisions. The purpose of this study was to evaluate sizing of primary breast cancer using mammography, sonography and magnetic resonance imaging (MRI) and thereby establish which imaging method most accurately corresponds with the size of the histological result.
Methods
Data from 121 patients with primary breast cancer were analysed in a retrospective study. The results were divided into the groups “ductal carcinoma in situ (DCIS)”, invasive ductal carcinoma (IDC) + ductal carcinoma in situ (DCIS)”, “invasive ductal carcinoma (IDC)”, “invasive lobular carcinoma (ILC)” and “other tumours” (tubular, medullary, mucinous and papillary breast cancer). The largest tumour diameter was chosen as the sizing reference in each case. Bland-Altman analysis was used to determine to what extent the imaging tumour size correlated with the histopathological tumour sizes.
Results
Tumour size was found to be significantly underestimated with sonography, especially for the tumour groups IDC + DCIS, IDC and ILC. The greatest difference between sonographic sizing and actual histological tumour size was found with invasive lobular breast cancer. There was no significant difference between mammographic and histological sizing. MRI overestimated non-significantly the tumour size and is superior to the other imaging techniques in sizing of IDC + DCIS and ILC.
Conclusions
The histological subtype should be included in imaging interpretation for planning surgery in order to estimate the histological tumour size as accurately as possible.
doi:10.1186/1471-2407-13-328
PMCID: PMC3704854  PMID: 23826951
Breast cancer; Tumour size; Sonography; Mammography; Magnetic resonance imaging; Ductal carcinoma in situ; Invasive ductal carcinoma; Invasive lobular carcinoma
21.  Cytodiagnosis of papillary carcinoma of the breast: Report of a case with histological correlation 
Papillary lesions of the breast pose diagnostic challenges on aspiration cytology due to overlapping features of benign and malignant entities. Accurate cytologic diagnosis of papillary breast carcinoma cannot usually be made pre-operatively. We present the case of an adult female who underwent fine-needle aspiration (FNA) of a left breast lump. FNA smears were highly cellular showing cohesive clusters, complex papillary fragments and few singly dispersed intact cells. The tumor cells had hyperchromatic nuclei, prominent nucleoli and mild nuclear pleomorphism. A cytologic impression of papillary lesion, possibly malignant (in view of high cellularity, complex papillae and single intact cells) was rendered. The lesion proved to be a papillary carcinoma with microscopic foci of stromal invasion on histologic examination. Papillary carcinoma, an uncommon subtype of breast carcinoma, should be considered while evaluating a papillary lesion with complex branching papillae containing delicate fibrovascular cores and singly lying intact atypical cells.
doi:10.4103/0970-9371.138694
PMCID: PMC4159896  PMID: 25210247
Aspiration cytology; breast; invasive; papillary carcinoma
22.  LIM only 4 is overexpressed in late stage pancreas cancer 
Molecular Cancer  2008;7:93.
Background
LIM-only 4 (LMO4), a member of the LIM-only (LMO) subfamily of LIM domain-containing transcription factors, was initially reported to have an oncogenic role in breast cancer. We hypothesized that LMO4 may be related to pancreatic carcinogenesis as it is in breast carcinogenesis. If so, this could result in a better understanding of tumorigenesis in pancreatic cancer.
Methods
We measured LMO4 mRNA levels in cultured cells, pancreatic bulk tissues and microdissected target cells (normal ductal cells; pancreatic intraepithelial neoplasia-1B [PanIN-1B] cells; PanIN-2 cells; invasive ductal carcinoma [IDC] cells; intraductal papillary-mucinous adenoma [IPMA] cells; IPM borderline [IPMB] cells; and invasive and non-invasive IPM carcinoma [IPMC]) by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR).
Results
9 of 14 pancreatic cancer cell lines expressed higher levels of LMO4 mRNA than did the human pancreatic ductal epithelial cell line (HPDE). In bulk tissue samples, expression of LMO4 was higher in pancreatic carcinoma than in intraductal papillary-mucinous neoplasm (IPMN) or non-neoplastic pancreas (p < 0.0001 for both). We carried out microdissection-based analyses. IDC cells expressed significantly higher levels of LMO4 than did normal ductal epithelia or PanIN-1B cells (p < 0.001 for both) or PanIN-2 cells (p = 0.014). IPMC cells expressed significantly higher levels of LMO4 than did normal ductal epithelia (p < 0.001), IPMA (p < 0.001) and IPMB cells (p = 0.003).
Conclusion
Pancreatic carcinomas (both IDC and IPMC) expressed significantly higher levels of LMO4 mRNA than did normal ductal epithelia, PanIN-1B, PanIN-2, IPMA and IPMB. These results suggested that LMO4 is overexpressed at late stages in carcinogenesis of pancreatic cancer.
doi:10.1186/1476-4598-7-93
PMCID: PMC2628350  PMID: 19099607
23.  Upgrade of high-risk breast lesions detected on mammography in the Breast Cancer Surveillance Consortium 
American journal of surgery  2013;207(1):10.1016/j.amjsurg.2013.05.014.
Background
Upgrade rates of high-risk breast lesions after screening mammography were examined.
Study design
The Breast Cancer Surveillance Consortium registry was used to identify all BI-RADS 4 assessments followed by needle biopsies with high-risk lesions. Follow-up was performed for all women.
Results
High-risk lesions were found in 957 needle biopsies, with excision documented in 53%. Most (N=685) were atypical ductal hyperplasia (ADH), 173 were lobular neoplasia, and 99 were papillary lesions. Upgrade to cancer varied with type of lesion (18% in ADH, 10% in lobular neoplasia and 2% in papillary). In premenopausal women with ADH, upgrade was associated with family history. Cancers associated with ADH were mostly (82%) ductal carcinoma in situ, those associated with lobular neoplasia were mostly (56%) invasive. During further 2 years of follow-up, cancer was documented in 1% of women with follow-up surgery and in 3% with no surgery.
Conclusion
Despite low rates of surgery, low rates of cancer were documented during follow-up. Benign papillary lesions diagnosed on BI-RADS 4 mammograms among asymptomatic women do not justify surgical excision.
doi:10.1016/j.amjsurg.2013.05.014
PMCID: PMC3865063  PMID: 24112677
24.  Papillary squamous cell carcinoma of the mandibular gingiva 
Papillary squamous cell carcinoma (PSCC) has rarely been reported in the oral cavity. Herein reported is a case of PSCC in the mandibular gum. A 70-year-old man consulted our hospital because of a papillary tumor in the left mandibular gum. Physical examination revealed an exophytic papillary tumor of the left mandibular gum, and an excision of the tumor was performed. Grossly, the tumor was exophytic and papillary, and measured 1 x 1 x 0.8 cm. Microscopically, the tumor showed exophytic papillary proliferation with fibrovascular cores and consisted of atypical squamous epithelial cells. The tumor cells showed hyperchromasia, nuclear atypia, mitotic figures, apoptotic bodies, cancer pearls, and individual keratinization. Mild stromal invasion was seen. Immunohistochemically, the tumor cells were positive for pancytokeratin AE1/3, pancytokeratin CAM5.2, p63, p53, and Ki-67 (labeling index=40%), but negative for human papilloma virus (HPV). HPV in situ hybridization revealed no signals. Therefore, PSCC was diagnosed. The lateral and vertical margins are negative for tumor cell. The pathological diagnosis was PSCC. The patient was healthy and free from tumor three months after the operation.
PMCID: PMC3438768  PMID: 22977668
Papillary squamous cell carcinoma; oral cavity
25.  D2-40: an additional marker for myoepithelial cells of breast and the precaution in interpreting tumor lymphovascular invasion 
D2-40 is a recently available mouse monoclonal antibody specific for human podoplanin and has been used in identifying lymphovascular invasion (LVI) of tumors. Although its expression has been evaluated in other tissues, its use as a marker for myoepithelial cells (MEC) of breast has not been studied. To explore its expression in the MEC of breast, paraffin-embedded tissue blocks from 48 patients with breast diseases were selected to include usual ductal hyperplasia (UDH, 41 cases), atypical ductal hyperplasia (ADH, 4 cases) and ductal carcinoma in situ (DCIS, 17 cases). Normal breast parenchyma and invasive carcinoma coexisting in the tissue sections were also included in the study. Immunohistochemistry for D2-40, calponin and p63 was performed and the staining patterns were reviewed and compared. D2-40 immunohistochemical staining is positive in the cytoplasm of MEC in UDH, ADH, and the majority of DCIS. The staining pattern of D2-40 is comparable with that of calponin, however D2-40 staining of MEC is weaker than that of calponin and with less background. In addition, myoepithelial cells and myofibroblasts at the edge of retraction spaces of DCIS are also stained by D2-40 that could be misinterpreted as tumor LVI. In conclusion, D2-40 immunohistochemistry reliably identifies the MEC of breast in a variety of lesions in a pattern similar to that of calponin and p63, and can be used as an additional MEC marker. Caution should be exercised when interpreting the staining of cells surrounding DCIS and carcinoma with retraction artifact.
PMCID: PMC3037204  PMID: 21326813
D2-40; myoepithelial cells; breast; lymphovascular invasion

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