Ductal Intraepithelial Neoplasia Research Articles

Risk perception of patients with ductal carcinoma in situ (DCIS) of the breast and their healthcare practitioners: The importance of histopathological terminology, and the gaps in our knowledge.

Despite ductal carcinoma in situ (DCIS) being a non-obligatory precursor of invasive breast carcinoma, its diagnosis generates substantial psychological distress. The limited knowledge about the natural history of DCIS contributes to the insufficient transmission of information about DCIS to patients and the general population. The uncertainty about the progression risk to invasive carcinoma hampers adequate communication by clinicians. Breast cancer-related mortality after a DCIS diagnosis is low. However, several studies have demonstrated that DCIS patients generally overestimate the risk of developing loco-regional recurrence or dying from breast cancer. Various factors contribute to this perceived risk. Despite the lack of infiltrative growth, DCIS is treated similarly to invasive breast cancer, with surgery, radiotherapy, and hormonal therapy. Additionally, the term 'carcinoma' in DCIS provokes anxiety. Incorrect risk perception by physicians may result in overtreatment. Here, we provide an overview of epidemiologic data on mortality after DCIS. We discuss the impact of the term 'ductal carcinoma in situ 'on patients' and physicians' perceptions of risk. The available evidence is mostly limited to patients within the Anglosphere. Recent studies, and European studies in particular, are scarce. We identify this as an area of interest for future large-scale European studies. We discuss the potential value of the "ductal intraepithelial neoplasia" (DIN) terminology, introduced in 1998. Although replacing the concept of 'DCIS' with the DIN terminology is unlikely to solve the entire problem of risk overestimation, it could be the first step to optimize doctor-patient communication and alter the current risk perception.

ABCD1 as a Novel Diagnostic Marker for Solid Pseudopapillary Neoplasm of the Pancreas.

The diagnosis of solid pseudopapillary neoplasm of the pancreas (SPN) can be challenging due to potential confusion with other pancreatic neoplasms, particularly pancreatic neuroendocrine tumors (NETs), using current pathological diagnostic markers. We conducted a comprehensive analysis of bulk RNA sequencing data from SPNs, NETs, and normal pancreas, followed by experimental validation. This analysis revealed an increased accumulation of peroxisomes in SPNs. Moreover, we observed significant upregulation of the peroxisome marker ABCD1 in both primary and metastatic SPN samples compared with normal pancreas and NETs. To further investigate the potential utility of ABCD1 as a diagnostic marker for SPN via immunohistochemistry staining, we conducted verification in a large-scale patient cohort with pancreatic tumors, including 127 SPN (111 primary, 16 metastatic samples), 108 NET (98 nonfunctional pancreatic neuroendocrine tumor, NF-NET, and 10 functional pancreatic neuroendocrine tumor, F-NET), 9 acinar cell carcinoma (ACC), 3 pancreatoblastoma (PB), 54 pancreatic ductal adenocarcinoma (PDAC), 20 pancreatic serous cystadenoma (SCA), 19 pancreatic mucinous cystadenoma (MCA), 12 pancreatic ductal intraepithelial neoplasia (PanIN) and 5 intraductal papillary mucinous neoplasm (IPMN) samples. Our results indicate that ABCD1 holds promise as an easily applicable diagnostic marker with exceptional efficacy (AUC=0.999, sensitivity=99.10%, specificity=100%) for differentiating SPN from NET and other pancreatic neoplasms through immunohistochemical staining.

Metformin inhibits neutrophil extracellular traps-promoted pancreatic carcinogenesis in obese mice

Obesity has been linked to a higher risk of pancreatic cancer. However, the mechanism by which obesity promote pancreatic carcinogenesis is still unclear. We investigated the effect of obesity on pancreatic carcinogenesis in Pdx1-Cre; LSL-KrasG12D+/− (KC) mice. Metformin was administrated to rescue the effects of obesity and NETs. The pro-tumorigenic effects of neutrophil extracellular traps (NETs) were further evaluated in vivo and vitro. We found that obesity significantly promoted the progression of murine pancreatic ductal intraepithelial neoplasia (mPanIN). The proliferation rate and epithelial-mesenchymal transition (EMT) of mPanIN ductal cells were increased in obese mice. More visceral adipocytes, PD-L1+ neutrophil infiltration and NETs formation were found in the pancreas of obese mice and visceral adipocytes could recruit neutrophils and promote NETs formation. The latter could induce an inflammatory response in ductal cells via TLR4-dependent pathways both in vivo and vitro, as demonstrated by upregulation of IL-1β. Metformin and DNase I significantly reversed the pro-tumorigenic effects of obesity and NETs in vivo and in vitro. Our study provides causal evidence for the contribution of obesity in promoting pancreatic carcinogenesis in genetic model and reveals the mechanism by NETs to regulate mPanIN progression.

Diagnostic performance of image-guided vacuum-assisted breast biopsy after neoadjuvant therapy for breast cancer: prospective pilot study.

Image-guided vacuum-assisted breast biopsy (VABB) of the tumour bed, performed after neoadjuvant therapy, is increasingly being used to assess residual cancer and to potentially identify to identify pathological complete response (pCR). In this study, the accuracy of preoperative VABB specimens was assessed and compared with surgical specimens in patients with triple-negative or human epidermal growth factor receptor 2 (HER2)-positive invasive ductal breast cancer after neoadjuvant therapy. As a secondary endpoint, the performance of contrast-enhanced MRI of the breast and PET-CT for response prediction was assessed. This single-institution prospective pilot study enrolled patients from April 2018 to April 2021 with a complete response on imaging (iCR) who subsequently underwent VABB before surgery. Those with a pCR at VABB were included in the primary analysis of the accuracy of VABB. The performance of imaging (MRI and PET-CT) was analysed for prediction of a pCR considering both patients with an iCR and those with residual disease at postneoadjuvant therapy imaging. Twenty patients were included in the primary analysis. The median age was 44 (range 35-51) years. At surgery, 18 of 20 patients showed a complete response (accuracy 90 (95 per cent exact c.i. 68 to 99) per cent). Only two patients showed residual ductal intraepithelial neoplasia of grade 2 and 3 respectively. In the secondary analysis, accuracy was similar for MRI and PET-CT (77 versus 78 per cent; P = 0.76). VABB in patients with an iCR might be a promising method to select patients for de-escalation of surgical treatment in triple-negative or HER2-positive breast cancer. The present results support such an approach and should inform the design of future trials on de-escalation of surgery.

Local recurrence of mammary Paget’s disease after nipple-sparing mastectomy and implant breast reconstruction: a case report and literature review

ObjectiveTo provide a rare case of local recurrent Paget’s disease after nipple-sparing mastectomy (NSM) with immediate breast reconstruction with 10 years of disease-free survival and to analyze the clinical and pathological characteristics.BackgroundMammary Paget’s disease can be considered a rare type of local recurrence after breast cancer treatment, both in cases of conservative surgery and NSM with immediate breast reconstruction (Lohsiriwat et al, Ann Surg Oncol 19:1850-1855, 2012). Recurrent patients who present with nipple-areolar Paget’s disease usually have unfavorable primary pathological characteristics and different latency periods. However, the recurrent status in patients with favorable primary pathological characteristics and the latency periods after NSM with immediate breast reconstruction are unclear.MethodsFirst, we present a case of local recurrent Paget’s disease in a young patient diagnosed with invasive breast carcinoma at age 30 who underwent NSM with primary silicone reconstruction. Then, the keywords “Paget’s disease” and “nipple-sparing mastectomy” were selected. Articles including the local recurrence of Paget’s disease after NSM were collected from the PubMed, Springer, and OVID databases, and the acquired relevant data were analyzed. We did not restrict our search by study design or publication date.ResultsFive studies describing 31 cases of local recurrent Paget’s disease after NSM with implant breast reconstruction were included. The mean patient age reported was 45 years, and the average latency period from NSM to the local recurrence of Paget’s disease was 40.2 months. Recurrent tumor histological features were Paget’s disease with ductal carcinoma in situ (DCIS) in 16 patients (50%), Paget’s disease without DCIS in 13 patients (40.6%), and Paget’s disease with ductal intraepithelial neoplasia (DIN) in 3 patients (9.4%). The primary tumor histological feature was estrogen receptor (ER)(−)/progesterone receptor (PR)(−)/human epidermal growth factor receptor (HER-2)(+) in 21 patients (77.8%). Neither locoregional relapse nor metastatic events were found in these recurrent patients who accepted NAC excision after 4–5 years of follow-up. Our reported case showed that the patient experienced pregnancy and lactation after primary adjuvant chemotherapy and endocrine therapy. However, she developed an eczematoid lesion in the NAC 120 months after breast surgery. The histopathological examination was consistent with Paget’s disease of the breast. Complete NAC and breast silicone prosthesis removal were performed. The patient accepted no systematic or local therapy and is currently alive. It is noteworthy that the biological features of the primary tumor were ER(+), PR(+), and HER-2(−); however, the recurrent tumor changed to ER(−), PR(−), and HER-2(+).ConclusionsThe local recurrence of Paget’s disease after NSM is uncommon; it may develop at a very early age and have a very long time to recurrence, as in our patient, who presented with recurrence 10 years after primary surgery. Surgeons should be wary of local recurrence of the nipple-areola complex after NSM in patients with ER-negative and HER-2-positive primary tumors. However, patients with ER/PR-positive and HER-2-negative tumors should not be neglected; we reported a case of an ER/PR-positive and HER-2-negative primary tumor, and ER-positive recurrent cases have the longest latency period. The local recurrence rate of Paget’s disease after NSM is low, and the prognosis is good in recurrent patients who accept further extensive NAC excision. Further systematic treatment was not considered for this patient.

Abstract PO-073: Inactivation of Notch4 attenuated pancreatic tumorigenesis in mice

Abstract Expression of the Notch family of receptors are often upregulated in pancreatic ductal adenocarcinoma (PDAC), however, the functional impacts of the Notch signaling network on pancreatic tumorigenesis remain unresolved. In this study, we focused on Notch4, which had not been investigated in PDAC. Leveraging the conventional Notch4 deficient mouse line and previously established genetically engineered mouse models (GEMM) for PDAC, we generated KC (LSL-KrasG12D;p48-Cre), N4−/−KC (Notch4−/−;LSL-KrasG12D;p48-Cre), PKC (p16flox/flox;LSL-KrasG12D;p48-Cre), and N4−/−PKC GEMMs (Notch4−/−; p16flox/lox;LSL-KrasG12D;p48-Cre). We performed caerulein treatment in both KC and N4−/−KC mice, and compared the development of acinar to ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) between them. The ADM/PanIN lesions were significantly smaller in the N4−/−KC than in the KC GEMM (p=0.01), suggesting that Notch4 deficiency attenuated early pancreatic tumorigenesis. This in vivo result was confirmed by in vitro ADM induction of the explant cultures of mouse pancreatic acinar cells. The number of ADM structures in the N4−/−KC acinar cultures was significantly lower than the KC acinar cultures (p<0.001). To evaluate the role of Notch4 in the later stage of pancreatic tumorigenesis, we compared the histological progression and overall survival between the PKC and N4−/−PKC mice. We found that N4−/−PKC mice had better prognosis (p=0.012) and less tumor burden (PanIN: p=0.018 (2 months), PDAC: p=0.039 (5 months)) compared to the PKC GEMM. RNA-Seq analysis of pancreatic tumor cell lines derived from the PKC and N4−/−PKC GEMMs revealed 408 genes were differentially expressed (FDR<0.05) and the genes related to the NGF processing as novel downstream effectors of the Notch4 signaling pathway(p<0.001). Our study is a novel biological investigation that demonstrated that Notch4 signaling possesses tumor promoting function in pancreatic tumorigenesis. Our study revealed a novel association between the NGF processing pathway and Notch4 signaling in PDAC. Citation Format: Kiyoshi Saeki, Wanglong Qiu, Richard Friedman, Carrie Shawber, Jan Kitajewski, Jianhua Hu, Gloria H. Su. Inactivation of Notch4 attenuated pancreatic tumorigenesis in mice [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-073.

Values of 5mC, 5hmC, and TET2 for identifying the presence and progression of breast precancerous lesion.

BackgroundThis study aimed to evaluate the correlations of 5‐methylcytosine (5mC), 5‐hydroxymethylcytosine (5hmC), and ten‐eleven translocation enzyme 2 (TET2) expressions in lesion tissue with histological classification of breast precancerous lesion.MethodsEighty‐three patients with breast ductal intraepithelial neoplasia (DIN), 20 patients with breast ductal carcinoma in situ with microinvasion (DCIS‐MI), and 10 patients with invasive breast cancer were included. Histological classification of the DIN patients was classified as DIN1A, DIN1B, DIN1C, DIN2, and DIN3. 5mC, 5hmC, and TET2 expressions in lesion tissues from biopsy were assessed by immunohistochemistry (IHC) assay.Results5hmC and TET2 were negatively associated with histological classification as validated by both IHC score and IHC semi‐quantification expression grades in total patients (all P < .05); however, no correlation of 5mC with histological classification was found (all P > .05). 5mC (P = .004) was negatively but 5hmC (P < .001) was positively correlated with TET2, while no association of 5mC with 5hmC was discovered in total patients (P = .078). In addition, 5mC was positively associated with ER expression in total patients (P = .040). In subgroups, 5mC was negatively correlated with 5hmC in DIN1C patients (P = .023) and invasive cancer patients (P = .044), and 5mC was negatively associated with TET2 in DIN1B patients (P = .004) as well as DCIS‐MI patients (P = .003).Conclusion5hmC and TET2 have the potentials to serve as biomarkers that could assist in the identification of presence and progression of breast precancerous lesion.

Breast Conserving Surgery and Intraoperative Electron Radiotherapy (IOERT) Among Cases of Ductal Carcinoma In Situ

Background: Ductal Carcinoma In Situ (DCIS) which has recently been renamed into Ductal Intraepithelial Neoplasia (DIN), is a malignant cell proliferation without invasion to basement membrane of ducts or lobules of breast. DCIS consists 20-30% of newly diagnosed breast cancers in some Western countries due to higher diagnosis resulting from screening by mammography. Relative Risk (RR) of invasive ductal carcinoma is 8-10 times in DCIS, although high grading lesions and positive or close surgical margins are two important predictive factors in DCIS recurrences. The adjuvant radiotherapy has decreased the rate of ipsilateral local recurrence about 60%. In this article, we evaluated the recurrence rate as DCIS as well as invasive breast cancer in patients with DCIS undergoing breast conserving surgery (BCS) and intraoperative electron radiotherapy (IOERT).Methods: Data were derived from Cancer Research Center database from 38 pure DCIS cases who had received intraoperative radiation therapy between 2012–2017. Intraoperative electron radiotherapy (IOERT) was performed according to Iran's intraoperative radiation therapy consensus.Results: The median age of the patients was 55 years and median histological lesion size was 1.8 centimeters. Number of extracted lymph nodes had a median of 1 and all extracted nodes were negative. Hormonal therapy was performed in 42.1% of patients. IOERT was done as radical full exposure for 86.9% of cases and as boost dose for 13.1% of cases, who needed to complete radiotherapy by external beam. One case in the group received boost dose and 4 cases in the group received full dose had recurrence. The median follow-up of patients was 31 months. Pathology of recurrence was reported as DCIS in 3 cases and invasive breast cancer in 2 of them.Conclusion: There is not a lot of data on the effectiveness of IOERT in DCIS management. Although there are not large number of cases in our study, the local recurrence (13.1%) was only event in our study with 31 months median follow up with no contralateral metastasis, distant metastasis, or death.

Malignant Intraductal Lesions in the Breast: Mini-Review

Malignant intraductal lesion of the breast is equal to Ductal carcinoma in situ (DCIS). And synonyms are Ductal intraepithelial neoplasia (DIN) and Intraductal carcinoma (IDC).

Abstract B06: Maintenance of acinar cell differentiation prevents KRAS-driven pancreatic cancer initiation

Abstract The primary goal of this study is to determine whether sustained expression of the acinar differentiation determinant, PTF1A, is sufficient to prevent and/or reverse KRAS-driven pancreatic cancer initiation. With a 5-year survival of only ~6%, pancreatic ductal adenocarcinoma (PDAC) remains one of the worst prognoses in medicine. In most clinical cases, PDAC is detected after the primary tumor has metastasized, leaving limited treatment options. Our lab is interested in understanding the initiating events that drive early tumorigenesis, which may provide new targets for early intervention. Activating mutations in the “un-druggable” proto-oncogene KRAS are found in over 90% of human PDAC cases, and expression of an oncogenic Kras mutant (KrasG12D) in the acinar epithelium of adult mice recapitulates formation of precancerous pancreatic intraepithelial neoplasia (PanIN) [1]. Because formation of PanINs takes months in these mouse models despite nearly ubiquitous KrasG12D expression, we hypothesized that acinar cell differentiation programs might suppress the transforming ability of this oncogene. Indeed, recent conditional-knockout studies from our lab demonstrate that downregulation of Ptf1a, the master transcriptional regulator of acinar cell differentiation, is rate-limiting for KRAS-driven PanIN formation and subsequent PDAC formation [2]. These findings suggest that acinar cell differentiation may serve as a barrier to tumor development by blocking the earliest phases of oncogenesis. We therefore hypothesized that sustaining Ptf1a expression during pancreatic cancer initiation/progression would inhibit or reverse disease. To test this hypothesis, we generated a Cre- and doxycycline-dependent Ptf1a gain-of function (GOF) mouse model on a KrasG12D background. Eight weeks after we induced recombination, mice expressing both oncogenic KrasG12D and GOF-Ptf1a had a significantly reduced PanIN burden compared to mice expressing KrasG12D alone, suggesting that preservation of acinar cell differentiation does limit pancreatic tumor initiation. Examination of PanINs in KrasG12D + GOF-Ptf1a pancreata revealed that PTF1A expression was completely lost in the few precancerous lesions that did form, suggesting that the cells contributing to these lesions were escapers that did not express transgenic Ptf1a. Taken together, these results suggest that silencing of Ptf1a is a necessary step in PDAC initiation. In ongoing studies, we are using KrasG12D + GOF-Ptf1a mice to test whether reintroduction of Ptf1a into established PanINs can revert these cells to a quiescent phenotype in vivo, and we will present these preliminary data at this meeting. Our results to date suggest that acinar differentiation provides a novel, epigenetic barrier to tumor initiation and highlight the potential importance of cell differentiation in solid tumors [3]. Going forward, we propose that studying cell differentiation in other tumor types may provide insight to disease initiation and potential treatment. 1. De La, O.J., et al., Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci U S A, 2008. 105(48): p. 18907-12. 2. Krah, N.M., et al., The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. Elife, 2015. 4. 3. Krah, N.M. and L.C. Murtaugh, Differentiation and inflammation: best enemies in gastrointestinal carcinogenesis. Under review. Citation Format: Nathan M. Krah, Deanne E. Yugawa, Julie A. Straley, Shuba M. Narayanan, Ana C. Azevedo-Pouly, L. Charles Murtaugh. Maintenance of acinar cell differentiation prevents KRAS-driven pancreatic cancer initiation [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B06.

MRI to predict nipple-areola complex (NAC) involvement: An automatic method to compute the 3D distance between the NAC and tumor.

To assess the role in predicting nipple-areola complex (NAC) involvement of a newly developed automatic method which computes the 3D tumor-NAC distance. Ninety-nine patients scheduled to nipple sparing mastectomy (NSM) underwent magnetic resonance (MR) examination at 1.5 T, including sagittal T2w and dynamic contrast enhanced (DCE)-MR imaging. An automatic method was developed to segment the NAC and the tumor and to compute the 3D distance between them. The automatic measurement was compared with manual axial and sagittal 2D measurements. NAC involvement was defined by the presence of invasive ductal or lobular carcinoma and/or ductal carcinoma in situ or ductal intraepithelial neoplasia (DIN1c - DIN3). Tumor-NAC distance was computed on 95/99 patients (25 NAC+), as three tumors were not correctly segmented (sensitivity = 97%), and 1 NAC was not detected (sensitivity = 99%). The automatic 3D distance reached the highest area under the receiver operating characteristic (ROC) curve (0.830) with respect to the manual axial (0.676), sagittal (0.664), and minimum distances (0.664). At the best cut-off point of 21 mm, the 3D distance obtained sensitivity = 72%, specificity = 80%, positive predictive value = 56%, and negative predictive value = 89%. This method could provide a reproducible biomarker to preoperatively select breast cancer patients candidates to NSM, thus helping surgical planning and intraoperative management of patients.

Ductal Spread Versus High-Grade Prostatic Intraepithelial Neoplasia: A Diagnostic Pitfall.

Ductal spread (DS) of acinar adenocarcinoma of the prostate can lead to an incomplete replacement of the benign epithelium by cancer cells, resulting in a lesion that can be indistinguishable from high-grade prostatic intraepithelial neoplasia (HGPIN). Kovi and colleagues demonstrated 30 years ago that there is a significant association between the presence of DS and local extent of invasive adenocarcinoma, making the distinction between DS and HGPIN clinically relevant. However, despite the existence of certain morphologic features that are suggestive of DS, a definitive differentiation between the aforementioned lesions cannot always be attained.

Co-expression of p16 and p53 characterizes aggressive subtypes of ductal intraepithelial neoplasia.

In the USA alone, approximately 61,000 new diagnoses of ductal intraepithelial neoplasia 1c-3 (DIN) are made each year. Around 10-20% of the patients develop a recurrence, about 50% of which are invasive. Prior studies have shown that invasive breast carcinomas positive for p16 or p53 have a higher frequency of recurrence and a more aggressive course; however, the co-expression of these markers across the entire spectrum of DIN and its potential correlation with grade of the lesions has not been studied previously. Immunohistochemical staining for p16 and p53 was evaluated on 262 DIN lesions from 211 cases diagnosed between 1991 and 2008. The lesions ranged from DIN1b (atypical intraductal hyperplasia) to DIN3 (DCIS, grade 3) and included 45 cases with associated invasive carcinoma. Frequency of staining for both p16 and p53 increased with increasing grade of DIN. Strong co-expression was found exclusively in higher grade DIN lesions (DIN2 and DIN3) particularly those associated with periductal stromal fibrosis and lymphocytic infiltrate. Strong co-expression was seen in 8 of 12 DIN3 lesions (67%) associated with invasive carcinoma. In conclusion, co-expression of p16 and p53 increases with advancing grade of DIN and is maximal in high grade DIN lesions associated with invasive carcinoma, indicating a more aggressive phenotype. A distinctive variant of DIN with periductal fibrosis and lymphocytic infiltrate invariably falls into the high-grade category, based on either morphology or marker expression. Co-expression of p16/p53 may be of help in distinguishing between high-grade and low-grade DIN lesions.

Distribution pattern of Ki67 immunoreactivity in ductal intraepithelial neoplasia: Correlation with lesion grade and potential utility

BackgroundIn this study, the pattern of distribution of the nuclei immunoreactive with Ki67 was examined in DIN1c (DCIS, grade 1/low grade), DIN2 (DCIS, grade 2/intermediate grade), and DIN3 (DCIS, grade 3/high grade). The lesions were evaluated to determine if distinctive patterns could be identified in correlation with lesion grade. MethodsFifty seven (n=57) consecutive DIN cases were investigated. Of these, 15 qualified as DIN1c, 28 as DIN2 and 14 as DIN3. The patterns of distribution were recorded for each case as either basal/peripheral or haphazard within the epithelial proliferation. ResultsThere was a statistically significant difference between the DIN1c, DIN2 and DIN3 in terms of basal/peripheral versus haphazard distribution of Ki67 immunostaining (Chi–square test, P<0.0001). Basal/peripheral staining pattern was dominant among the DIN1c cases, while haphazard staining pattern was the dominant distribution among the DIN3 cases. One half of the DIN2 cases showed basal/peripheral staining pattern, while the other half showed a haphazard staining pattern. ConclusionHigh grade DIN lesions show haphazard Ki67 staining while low grade DIN lesions show basal/peripheral Ki67 staining in the proliferating epithelial cells. This feature could be practical in separating DIN lesions into low grade (basal/peripheral-Ki67) and high grade (haphazard-Ki67) eliminating the grade 2/intermediate category.

Expression of C-KIT, CD24, CD44s, and COX2 in benign and non-invasive apocrine lesions of the breast.

Benign apocrine metaplasia (AM) of the adult breast is a very common, but enigmatic lesion. It has been speculated that AM might be a precursor of malignancy or an indicator of a susceptibility of the breast tissue to develop neoplasia, mainly based on comparing the frequency of AM in breast cancer and non-breast cancer patients [1]. Studies using comparative genomic hybridization have supported this by showing similar molecular alterations in benign and malignant apocrine lesions [2]. Few studies, however, have compared expression of biomarkers involved in tumor progression in AM and progressively more advanced atypical apocrine lesions. The expression of C-KIT, COX2, CD24, and CD44s was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded material of 9 AM, 20 apocrine ductal intraepithelial neoplasia (DIN1c-3) and 40 atypical apocrine lesions (not qualifying for DIN1c-3) and compared to expression of the same biomarkers in adjacent normal ductal epithelium. Of the 66 apocrine lesions, 62 (94%) did not express C-KIT compared to 4/63 (6%) of the normal glands (Fisher's exact, p < 0.001). COX2 was expressed in a significantly higher proportion of apocrine lesions than of normal glands (49 vs. 14%, p < 0.001), and the number of apocrine lesions positive for CD24 was found to be higher with increasing aggressiveness of the lesions (Spearman, p < 0.001). In conclusion, benign and non-invasive proliferative apocrine lesions of the breast display immuno-phenotypical characteristics previously ascribed mainly to malignant transformation. This could lend support to the theory that AM is an early step towards malignant transformation, albeit associated with slow progression to carcinoma.

Abstract P1-01-07: Distribution pattern of Ki67 immunoreactivity in ductal intraepithelial neoplasia (DIN): Correlation with lesion grade and potential utility

Abstract INTRODUCTION: Ki67 labeling index has been proposed as an independent predictive and prognostic factor in patients with ductal intraepithelial neoplasia (DIN). Ki-67 labeling index of 14% has been suggested as a useful cut-off for stratifying DIN patients for adjuvant radiotherapy and hormonal therapy. No data is available regarding either the distribution pattern of Ki67 immunoreactivity within the ducts involved by DIN or potential correlation of these patterns with lesion grade. In this study, the pattern of distribution of the nuclei immunoreactive with Ki67 was examined in DIN1C (DCIS, grade 1), DIN2 (DCIS, grade2), and DIN3 (DCIS, grade 3) to determine if distinctive patterns could be identified and if these patterns would correlate with lesion grade. METHODS: 47 consecutive DIN cases were retrieved from our departmental files. Of these, 5 qualified as DIN1C, 28 as DIN2 and 14 as DIN3. H&amp;E and Ki67 immunostains were evaluated on each case to elucidate the distribution of Ki67 positive proliferating epithelial cells within the ducts. The DIN cases were evaluated and the patterns of distribution recorded for each case as either basal or haphazard within the epithelial proliferation. Statistical analysis was performed using Chi-square test with Graphpad PRISM statistical analysis software. RESULTS: There was a statistically significant difference between the 3 groups in terms of basal vs haphazard Ki67 immunostaining (Chi –square test, P=0.0001). Basal staining pattern was dominant (100%) among the DIN1c cases, while haphazard staining pattern was the dominant (100%) distribution among the DIN3 cases. One half of the DIN2 cases showed basal staining pattern, while the other half showed a haphazard staining pattern. This feature could be useful in separating DIN lesions into low grade and high grade eliminating grade 2. We also quantified necrosis on a scale of 0 to 2; 0 indicating absence of necrosis and 2 reflecting comedo type necrosis. Necrosis was more common in the ducts with haphazard Ki67 distribution. The extent of necrosis varied significantly between DIN1c, DIN2 and DIN3 (Chi –square test, P&amp;lt;0.0001) CONCLUSIONS: Two distinct patterns of Ki67 immunoreactivity are seen in DIN lesions; the basal pattern is characteristic of DIN1 (low grade DIN), whereas a haphazard pattern is dominant in DIN3 (high grade DIN). These patterns could be used to divide grade 2 DIN into low grade and high grade. This approach is easier and potentially more reproducible than counting the percentage of Ki67 positive cells. The information could be useful from a prognostic standpoint and may well be predictive of potential response to radiation, hormonal and targeted therapies. Citation Format: Ozerdem U, Tavassoli FA. Distribution pattern of Ki67 immunoreactivity in ductal intraepithelial neoplasia (DIN): Correlation with lesion grade and potential utility. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-01-07.

Abstract P1-01-08: An impending avalanche-breast cancer among women ≥ 90 years of age

Abstract INTRODUCTION: Pubmed database shows no study on pathological features of breast carcinoma in extremely old women (≥90 years). The data post 1980s is limited due to the definition of such age limit as "older than 75". This study redefines age extreme in breast pathology to better correlate with current patient demographics, and provides characteristics of breast cancer in this population. Little information exists about the breast cancer in extremely old women. This investigation elucidates the growing number of breast cancer diagnoses in extremely old women (≥90 years) in a single institution in 2000s. MATERIALS AND METHODS: The database of Yale University Department of Pathology was searched for the terms: "breast carcinoma," "age ≥90" for the past 15 years. Clinicopathologic features of the cases that fit the criteria were studied. RESULTS: A total of 135 patients (134 female; 1 male) aged ≥90 years were identified with a diagnosis of infiltrating carcinoma. A surge in breast cancer diagnoses among elderly patients was noted in 2000s compared to the earlier decade. Only 10 cases were diagnosed between 1990 and 1999 (one case/year) compared to 125 cases diagnosed between 2000 and 2015 (8.3 cases/year). Of these 135 patients, 117 had infiltrating ductal carcinoma (IDC); 16 had infiltrating lobular carcinoma (ILC),1 had pure squamous cell carcinoma. One patient had IDC and ILC ipsilaterally, while another had bilateral IDC. The median age was 92 (range: 90-107), median tumor size was 2.0 cm (range: 0.2-13.0), and the median modified Bloom &amp; Richardson score was 6 (range: 3-9). Among the 117 IDCs, 11 had mucinous, 6 had apocrine, 1 had medullary, 1 had cribriform differentiation. Ductal intraepithelial neoplasia (DCIS) was present in 46% of the cases, while lobular intraepithelial neoplasia (LCIS) was identified in 8% of the cases. CONCLUSIONS: Our data shows an increasing number of breast carcinomas diagnosed among patients ≥90 years of age with a morphological distribution similar to other age groups. This increased frequency is particularly notable in the last 15 years compared to 1990s. While increased life expectancy is a factor, better delivery of screening to elderly patients and patient awareness are important additional contributors to this increase. Extremely old women particularly those in good health may potentially benefit from breast cancer screening. As the number of substantially older patients with breast cancer increases, we have to be prepared to manage the disease in this population. Further studies are warranted to elucidate the frequency of breast cancer in extremely old women and the optimal management that would probably have to be individualized to the patients' health status. Citation Format: Ozerdem U, Tavassoli FA. An impending avalanche-breast cancer among women ≥ 90 years of age. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-01-08.

Cytokeratin 7-negative mammary Paget's disease: A diagnostic pitfall

Pathologists should be aware of the existence of a rare CK7-negative variant of breast carcinoma in general, and of Paget's disease in particular. Cytokeratin 7-negative Paget's disease and CK7-negative ductal intraepithelial neoplasia (ductal carcinoma in situ) present a major diagnostic challenge for pathologists since there is limited awareness of their existence. When there is classic Paget's morphology on H&E sections, GATA3 positivity should resolve any doubts about the diagnosis in the setting of a CK7-negative neoplastic cell population.

Eliminating “ductal carcinoma in situ” and “lobular carcinoma in situ” (DCIS and LCIS) terminology in clinical breast practice: The cognitive psychology point of view

There is evidence from the literature that the terms “ductal carcinoma in situ” and “lobular carcinoma in situ” (DCIS and LCIS) should be eliminated in clinical breast cancer practice and replaced with the new “ductal intraepithelial neoplasia” (DIN) and “lobular intraepithelial neoplasia” (LIN) terminology. The main purpose of the present article is to expand on this argument from a cognitive psychology perspective and offer suggestions for further research, emphasizing how the elimination of the term “carcinoma” in “in situ” breast cancer diagnoses has the potential to reduce both patient and health care professional confusion and misperceptions that are often associated with the DCIS and LCIS diagnoses, as well as limit the adverse psychological effects of women receiving a DCIS or LCIS diagnosis. We comment on the recent peer-reviewed literature on the clinical implications and psychological consequences for breast cancer patients receiving a DCIS or LCIS diagnosis and we use a cognitive perspective to offer new insight into the benefits of embracing the new DIN and LIN terminology. Using cognitive psychology and cognitive science in general, as a foundation, further research is advocated in order to yield data in support of changing the terminology and therefore, offer a chance to significantly improve the lives and psychological sequelae of women facing such a diagnosis.Typology: Controversies/Short Commentary

Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ Progression

We describe a preclinical model that investigates progression of early-stage ductal carcinoma in situ (DCIS) and report that compromised myoepithelial cell differentiation occurs before transition to invasive disease. Human breast cancer MCF10DCIS.com cells were delivered into the mouse mammary teat by intraductal injection in the absence of surgical manipulations and accompanying wound-healing confounders. DCIS-like lesions developed throughout the mammary ducts with full representation of human DCIS histologic patterns. Tumor cells were incorporated into the normal mammary epithelium, developed ductal intraepithelial neoplasia and DCIS, and progressed to invasive carcinoma, suggesting the model provides a rigorous approach to study early stages of breast cancer progression. Mammary glands were evaluated for myoepithelium integrity with immunohistochemical assays. Progressive loss of the myoepithelial cell differentiation markers p63, calponin, and α-smooth muscle actin was observed in the mouse myoepithelium surrounding DCIS-involved ducts. p63 loss was an early indicator, calponin loss intermediate, and α-smooth muscle actin a later indicator of compromised myoepithelium. Loss of myoepithelial calponin was specifically associated with gain of the basal marker p63 in adjacent tumor cells. In single time point biopsies obtained from 16 women diagnosed with pure DCIS, a similar loss in myoepithelial cell markers was observed. These results suggest that further research is warranted into the role of myoepithelial cell p63 and calponin expression on DCIS progression to invasive disease.