Neoadjuvant Chemotherapy or Endocrine Therapy for Invasive Ductal Carcinoma of the Breast With High Hormone Receptor Positivity and Human Epidermal Growth Factor Receptor 2 Negativity.

Importance: Although neoadjuvant endocrine therapy (NET) is an alternative to chemotherapy for strongly hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (ERBB2)-negative breast cancer, evidence is currently lacking regarding the probable survival outcomes of NET in comparison with those of neoadjuvant chemotherapy (NACT) for this cancer. Objective: To evaluate all-cause mortality among patients with strongly HR-positive and ERBB2-negative breast cancer treated with NET vs NACT. Design, Setting, and Participants: This cohort study included patients with a diagnosis of invasive ductal carcinoma (IDC) with strong HR positivity and ERBB2 negativity, treated between January 1, 2009, and December 31, 2016, with follow-up from the index date (ie, date of IDC diagnosis) to December 31, 2018. The data came from the Taiwan Cancer Registry Database. Data were analyzed from January to November 2020. Exposures: NET vs NACT for IDC with strong HR positivity and ERBB2 negativity. Main Outcomes and Measures: The primary end point was all-cause mortality. Propensity score matching was performed, and Cox proportional hazard models were used to analyze all-cause mortality among patients undergoing different neoadjuvant treatments. Results: A total of 640 patients (297 [46.4%] aged 20-49 years) undergoing NET (145 patients [22.7%]) or NACT (495 patients [77.3%]) were eligible for further analysis. In the multivariate Cox regression analyses, the adjusted hazard ratio (aHR) for all-cause mortality among the NET cohort compared with the NACT cohort was 2.67 (95% CI, 1.95-3.51; P < .001). The aHRs for age were 1.13 (95% CI, 1.03-2.24), 1.25 (95% CI, 1.13-2.45), and 1.37 (95% CI, 1.17-3.49) for all-cause mortality among patients aged 50 to 59, 60 to 69, and 70 years or older, respectively, compared with those aged 20 to 49 years (P = .002); the aHR for all-cause mortality among premenopausal women was 1.35 (95% CI, 1.13-1.56) compared with postmenopausal women (P < .001); and that of patients with a Charlson Comorbidity Index score of 2 or greater was 1.77 (1.37-2.26) compared with those with a score of 0 (P < .001). The aHRs of all-cause mortality for clinical tumor stage 2, 3, and 4 compared with 1 were 1.84 (95% CI, 1.07-3.40), 1.97 (95% CI, 1.03-3.77), and 2.49 (95% CI, 1.29-4.81), respectively (P = .009). The aHRs for all-cause mortality by clinical nodal (cN) stages were 1.49 (95% CI, 1.13-1.99) and 1.84 (95% CI, 1.31-2.61) for cN stage 1 and cN stages 2 or 3, respectively, compared with cN stage 0 (P = .005); those for differentiation were 1.77 (95% CI, 1.24-2.54) and 2.31 (95% CI, 1.61-3.34) for differentiation grade 2 and differentiation grade 3, respectively, compared with differentiation grade 1 (P < .001). Conclusions and Relevance: The findings of this study suggest that for patients with strongly HR-positive and ERBB2-negative IDC, NACT may be considered the first choice for neoadjuvant treatment.

The Myoepithelial Cells of Salivary Intercalated Duct-type Intraductal Carcinoma Are Neoplastic: A Study Using Combined Whole-slide Imaging, Immunofluorescence, and RET Fluorescence In Situ Hybridization.

Intraductal carcinoma (IDC) is a salivary gland tumor currently believed to be analogous to breast ductal carcinoma in situ, consisting of a complex neoplastic epithelial proliferation surrounded by a continuous layer of myoepithelial cells presumed to be native and non-neoplastic. Recent molecular insights have shown that there are at least 3 different types of IDC: (1) intercalated duct-like, with frequent NCOA4-RET fusions; (2) apocrine, with multiple mutations similar to salivary duct carcinoma; and (3) mixed intercalated duct-like and apocrine with frequent RET fusions, especially TRIM27-RET. Recent observations (eg, IDC occurring in lymph nodes) have challenged the notion that the myoepithelial cells of IDC are non-neoplastic. Five IDCs with known RET fusions by RNA sequencing were retrieved from the authors' archives, including 4 intercalated duct-like IDCs with NCOA4-RET, and 1 mixed intercalated duct-like/apocrine IDC with TRIM27-RET. A panel of immunohistochemistry antibodies (S100 protein, p63 or p40, mammaglobin, smooth muscle actin, calponin, androgen receptor) was tested. To precisely localize RET split-positive cells, each case was subjected to sequential retrieval of whole-slide imaging data of hematoxylin and eosin (HE) staining, immunofluorescence staining for calponin, and fluorescence in situ hybridization (FISH) for RET. Because NCOA4-RET is an inversion difficult to visualize on conventional RET FISH, a novel 3-color FISH technique was utilized to demonstrate it clearly. In all 5 cases, the proliferative ducts were completely surrounded by a layer of myoepithelial cells that were positive for p63 or p40, smooth muscle actin, and calponin. Using combined HE, calponin immunofluorescence, and RET FISH imaging, the positive signals were unmistakably identified in both calponin-negative ductal cells and peripheral, calponin-positive myoepithelial cells in all 5 cases. Utilizing combined HE, calponin immunofluorescence, and RET FISH imaging, we demonstrated that IDCs with RET fusions harbored this alteration in both the ductal and myoepithelial cells. This is compelling evidence that the myoepithelial cells of IDC are not mere bystanders, but are rather a component of the neoplasm itself, similar to other biphasic salivary gland neoplasms like pleomorphic adenoma and epithelial-myoepithelial carcinoma. This finding raises questions about the appropriate terminology, classification, and staging of IDC.

High EZH2 expression in ductal carcinoma in situ diagnosed on breast core needle biopsy is an independent predictive factor for upgrade on surgical excision.

PURPOSE: Approximately 25 % of DCIS diagnosed on breast core needle biopsy (CNB) is upgraded to invasive carcinoma on surgical excision. Risk factors to predict the upgrade on excision are not well established, leading many patients to be over or under-treated. EZH2 was shown to be associated with aggressive behavior of cancer from many sites, including breast cancer. We aimed to analyze EZH2 expression and tumor infiltrating lymphocytes (TILs) in DCIS as predictive factors for an upgrade on excision. METHODS: We assessed EZH2 expression in 34 DCIS cases diagnosed on CNB and upgraded to invasive carcinoma on excision. Then, we compared these cases with 60 control cases that were not upgraded on excision. A staining score for DCIS (0-12) was obtained by multiplying the staining intensity (0-3) and the percentage of positive cells (1-4). The nuclear staining score ≥6 was considered as 'high' expression. RESULTS: 46 of 94 (49 %) DCIS on CNB showed high EZH2 expression. EZH2 expression was directly correlated with TILs density, nuclear grade, HER2 expression, Ki-67 index and negative ER status. On univariate analysis, upgrade on excision was associated with high EZH2 expression, high TILs density, negative ER status and high Ki-67 index. Multivariate analysis revealed the high EZH2 expression as the only independent predictive factor for upgrade on excision. CONCLUSIONS: Our study revealed the high EZH2 expression as the only independent predictive factor for an upgrade on excision. Future studies should focus on the evaluation of EZH2 expression in tumor-microenvironment interaction in terms of diagnostic, treatment and prognostic purposes.

Clinicopathological study of intraductal carcinoma of the salivary gland, with emphasis on the apocrine type.

Intraductal carcinoma (IC) is a rare salivary gland tumor with low- to intermediate-grade cytological features. It is further classified into intercalated duct type and apocrine type based on its distinct histologic and immunohistochemical expression. Conventional salivary duct carcinoma (SDC) is an aggressive carcinoma with high-grade features and is usually associated with poor prognosis. In this study, immunohistochemistry and mutation analyses (including HRAS/PIK3CA mutations, RET rearrangement, and human epidermal growth factor receptor 2 [HER2] amplification) of 9 ICs (including 3 pure ICs, 6 ICs with invasive carcinoma) and 24 conventional SDCs were performed and the results were compared. Four intercalated duct-type cases were positive for SOX10 and S100 and negative for AR; five apocrine-type cases showed opposite results. All five apocrine-type cases had cysts with relatively circumscribed tumor borders and morphologically mimicking breast low-grade ductal carcinoma in situ or papillary carcinoma. RET fusion is detected in half of the 4 intercalated duct-type IC but not in the apocrine-type or conventional SDC. HER2 amplification was only observed in conventional SDC. The monoclonal antibody (clone RBT-NRAS) against NRAS Q61R is a sensitive and specific marker used for detecting HRAS Q61R mutation in the salivary gland tumors. The apocrine-type IC had different cytological grades, distinct tumor growth patterns, and no evidence of low- to high-grade transition, suggesting that apocrine-type IC should be distinguished from apocrine SDC with an in situ component.

Reporting Practices and Resource Utilization in the Era of Intraductal Carcinoma of the Prostate: A Survey of Genitourinary Subspecialists.

Intraductal carcinoma of the prostate (IDC-P) has been recently recognized by the World Health Organization classification of prostatic tumors as a distinct entity, most often occurring concurrently with invasive prostatic adenocarcinoma (PCa). Whether documented admixed with PCa or in its rare pure form, numerous studies associate this entity with clinical aggressiveness. Despite increasing clinical experience and requirement of IDC-P documentation in protocols for synoptic reporting, the specifics of its potential contribution to assessment of grade group (GG) and cancer quantitation of PCa in both needle biopsies (NBx) and radical prostatectomy (RP) specimens remain unclear. Moreover, there are no standard guidelines for incorporating basal cell marker immunohistochemistry (IHC) in the diagnosis of IDC-P, either alone or as part of a cocktail with AMACR/racemase. An online survey containing 26 questions regarding diagnosis, reporting practices, and IHC resource utilization, focusing on IDC-P, was undertaken by 42 genitourinary subspecialists from 9 countries. The degree of agreement or disagreement regarding approaches to individual questions was classified as significant majority (>75%), majority (51% to 75%), minority (26% to 50%) and significant minority (≤25%). IDC-P with or without invasive cancer is considered a contraindication for active surveillance by the significant majority (95%) of respondents, although a majority (66%) also agreed that the clinical significance/behavior of IDC-P on NBx or RP with PCa required further study. The majority do not upgrade PCa based on comedonecrosis seen only in the intraductal component in NBx (62%) or RP (69%) specimens. Similarly, recognizable IDC-P with GG1 PCa was not a factor in upgrading in NBx (78%) or RP (71%) specimens. The majority (60%) of respondents include readily recognizable IDC-P in assessment of linear extent of PCa at NBx. A significant majority (78%) would use IHC to confirm or exclude intraductal carcinoma if other biopsies showed no PCa, while 60% would use it to confirm IDC-P with invasive PCa in NBx if it would change the overall GG assignment. Nearly half (48%, a minority) would use IHC to confirm IDC-P for accurate Gleason pattern 4 quantitation. A majority (57%) report the percentage of IDC-P when present, in RP specimens. When obvious Gleason pattern 4 or 5 PCa is present in RP or NBx, IHC is rarely to almost never used to confirm the presence of IDC-P by the significant majority (88% and 90%, respectively). Most genitourinary pathologists consider IDC-P to be an adverse prognostic feature independent of the PCa grade, although recommendations for standardization are needed to guide reporting of IDC-P vis a vis tumor quantitation and final GG assessment. The use of IHC varies widely and is performed for a multitude of indications, although it is used most frequently in scenarios where confirmation of IDC-P would impact the GG assigned. Further study and best practices recommendations are needed to provide guidance with regards to the most appropriate indications for IHC use in scenarios regarding IDC-P.

PIN-like (Ductal) Adenocarcinoma of the Prostate.

Prostatic intraepithelial neoplasia like (PIN-like ductal) carcinoma are rare tumors characterized by crowded, often cystically dilated glands architecturally resembling high-grade prostatic intraepithelial neoplasia, lined by malignant pseudostratified columnar epithelium. The largest prior series studied 9 radical prostatectomies (RPs) and suggested a behavior similar to Gleason score 6. We sought to investigate this rare tumor within a larger series. PIN-like carcinoma cases were identified from in-house and consultation files from 2008 to 2017. A total of 190 total cases were identified (in-house cases n=8, 4.2%, consult cases n=182, 95.8%); the diagnosis of PIN-like carcinoma was made on needle biopsy (n=181), transurethral resection (n=5) and RP (n=4). The average age was 70 years. The average number of cores with involvement by PIN-like carcinoma was 2 (1 to 12). The average maximum percentage by a PIN-like carcinoma component of any core was 43.5% (5% to 90%). In 58/181 (32.0%) biopsy cases, due to selective parts having been submitted for consultation, it was unknown whether there was an association with acinar carcinoma. A total of 72 cases showed exclusively PIN-like carcinoma. Highest grade groups (GGs) on biopsies with known acinar or papillary/cribriform ductal carcinomas were GG1 (n=23, 45.1%), GG2 (n=14, 27.5%), GG3 (n=9, 17.6%), GG4 (n=4, 7.8%), and GG5 (n=1, 2.0%). Of 44 cases where the patient would be considered eligible for active surveillance, 18 (41.0%) underwent RP. RP slides were available in 16 cases; 3 (18.8%) cases diagnosed on biopsy did not show PIN-like carcinoma on review of RP slides. PIN-like carcinoma was present without an associated acinar tumor in 3 (23.1%) RPs; 2 showing tumors with large, cystic dilated glands extending into periprostatic tissue. In 7/13 cases (53.8%), the acinar component was the dominant tumor and the PIN-like carcinoma component was small (<1 cm). The overall grade at RP was GG1 (5/13, 38.5%) and GG2 (8/13, 61.5%). In all cases with an acinar component, the acinar tumor was anatomically distinct from the PIN-like carcinoma tumor. The GGs of the separate acinar tumors were GG1 (6/10) and GG2 (4/10) with percent pattern 4 ≤5% in all 4 cases. No cases were associated with metastases to lymph nodes or seminal vesicle invasion. Extraprostatic extension was present in 6/13 (46.1%) cases, from the acinar component in 1 (7.7%) case and the PIN-like carcinoma component in 5 (83.3%) cases. In all 5 cases, there was a peculiar morphology of thin papillary projections into cystic dilated PIN-like carcinoma glands. Immunohistochemical expression of ERG was positive in 1/11 (9.1%) case. 1/11 (9.1%) case showed heterogeneous loss of PTEN. Overall, PIN-like carcinoma tumors are limited in size, not advanced in stage, not associated with high-grade cancer on RP, and show low rates of Gleason pattern 4 and TMPS-ERG rearrangement. Our study supports grading classic PIN-like carcinoma as Gleason pattern 3; at the current time we recommend grading thin papillary projections of PIN-like carcinoma as pattern 4. Longer term studies will be needed to determine the clinical significance of thin papillary projections in PIN-like carcinoma.

Comedonecrosis Revisited: Strong Association With Intraductal Carcinoma of the Prostate.

From the advent of the Gleason grading system for prostate cancer, cancer displaying intraluminal necrotic cells and/or karyorrhexis within cribriform/solid architecture, a phenomenon termed "comedonecrosis," has been assigned pattern 5. Intraductal carcinoma (IDC-P) shows morphologic overlap with high-grade cribriform/solid adenocarcinoma architecturally and cytologically and may also show central necrosis, yet due to the presence of basal cells at the duct periphery is not currently assigned a grade in clinical practice. On the basis of observations from routine clinical cases, we hypothesized that comedonecrosis was more significantly associated with IDC-P than invasive disease. From a large series of mapped radical prostatectomy specimens (n=933), we identified 125 high-grade (≥Gleason score 4+3=7), high-volume tumors with available slides for review. All slides were examined for the presence of unequivocal comedonecrosis. Standard immunohistochemistry for basal cell markers was performed to detect basal cell labeling in these foci. In total, 19 of 125 (15%) cases showed some ducts with comedonecrosis-9 cases with 1 focus and 10 cases with ≥2 foci; in all, a total of 73 foci of true comedonecrosis were evaluated. Immunohistochemical stains revealed labeling for basal cell markers in a basal cell distribution for at least some comedonecrosis foci in 18 of 19 (95%) cases, 12 with IDC-P exclusively and 6 with a mix of IDC-P and invasive carcinoma comedonecrosis foci. These results suggest that comedonecrosis is strongly associated with IDC-P and hence, the routine assignment of pattern 5 to carcinoma exhibiting comedonecrosis should be reconsidered.

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a marker that predicts presence of invasion in papillary biliary tumors.

Biliary tumors showing intraductal papillary growth (Pap-BTs) include intraductal papillary neoplasm of the bile duct (IPNB) and papillary cholangiocarcinoma (CC). A differential diagnosis between IPNB and papillary CC currently remains challenging. The aim of the present study is to identify histological features and immunohistochemical markers of malignant potential such as tumor invasion in Pap-BTs. Subjects comprised 37 patients with Pap-BT (intrahepatic and perihilar [proximal], 27: 17 noninvasive and 10 invasive; distal, 10: all invasive). We examined histological features and the expression of p53, enhancer of zeste homolog 2, insulin-like growth factor II mRNA-binding protein 3 (IMP3), and DNA methyltransferase-1 in the intraductal area in Pap-BTs. Noninvasive Pap-BT was characterized by the presence of a low-grade dysplastic area, edematous stroma, and the absence of necrosis. The expression of p53, enhancer of zeste homolog 2, IMP3, and DNA methyltransferase-1 was significantly weaker in noninvasive Pap-BTs than in invasive Pap-BTs (P<.01). Diffuse cytoplasmic IMP3 expression was absent in noninvasive Pap-BTs. IMP3 showed the greatest specificity to predict a presence of invasion. A heatmap demonstrated that proximal noninvasive Pap-BTs and distal Pap-BTs may be completely different. In bile duct biopsies, the expression of IMP3 was the most precise predictor of invasion in Pap-BTs. In conclusion, Pap-BTs may be separated into 3 subgroups: (1) proximal noninvasive Pap-BT, corresponding to IPNB; (2) distal invasive Pap-BT, corresponding to papillary CC; and (3) the remaining Pap-BT including IPNB with associated adenocarcinomas, based on histological and immunohistochemical features. IMP3 may be a useful marker for predicting invasion in Pap-BT.

Intraductal Carcinoma of the Prostate Gland: Recent Advances.

Intraductal carcinoma of the prostate (IDC-P) is characterized by prostatic carcinoma involving ducts and/or acini. The presence of IDC-P is usually associated with a high-grade Gleason score, large tumor volume, and adverse prognostic parameters, including extraprostatic extension and seminal vesicle invasion. When present, IDC-P is associated with worse outcomes, regardless of treatment status. IDC-P is included in a broader diagnostic category of atypical cribriform lesions of the prostate gland. This category of lesions also includes high-grade prostatic intraepithelial neoplasia (HGPIN), urothelial carcinoma involving prostatic ducts or acini, and prostatic ductal adenocarcinoma, amongst other intraductal proliferations. Differentiating between these entities is important as they have differing therapeutic and prognostic implications for patients, although differential diagnosis thereof is not always straightforward. The present review discusses IDC-P in regards to its morphological characteristics, molecular features, and clinical outcomes. Given the current state of knowledge, the presence of IDC-P should be evaluated and documented correctly in both radical prostatectomy and needle biopsy specimens, and the clinical implications thereof should be taken into consideration during treatment and follow up.

Consistent PLAG1 and HMGA2 abnormalities distinguish carcinoma ex-pleomorphic adenoma from its de novo counterparts.

Carcinoma ex-pleomorphic adenoma (CA ex-PA) is a malignant salivary gland tumor that arises in association with pleomorphic adenoma (PA). Both PA and CA ex-PA have a broad spectrum of histology, and distinction from their histologic mimics may be difficult based on morphology alone. PLAG1 and HMGA2 abnormalities are the most common genetic events in both PA and CA ex-PA; however, the use of PLAG1 and HMGA2 as adjunct molecular tests has not been well established. Fluorescence in situ hybridization for PLAG1 and HMGA2 was performed on 22 CA ex-PA (10 myoepithelial carcinomas [MECAs], 10 salivary duct carcinomas [SDCs], 1 carcinoma with squamoglandular features, and 1 mixed MECA-adenocarcinoma not otherwise specified), 20 de novo carcinomas (11 MECAs and 9 SDCs), 16 PAs, and 11 PA-histologic mimics. All except 3 CAs ex-PA (86%) were positive for PLAG1 or HMGA2 rearrangements/amplifications. In contrast, 18 (90%) of 20 de novo carcinomas lacked abnormalities in PLAG1 or HMGA2 (P < .01). PLAG1 or HMGA2 rearrangements were identified in 6 (67%) of 9 hypocellular myxoid PAs and in 2 (29%) of 7 cellular PAs. Furthermore, all morphologic mimics of PA were negative for PLAG1 or HMGA2. PLAG1 and HMGA2 rearrangements are the most common genetic events in CA ex-PA regardless of the histologic subtype. Unlike CA ex-PA, de novo carcinomas were negative for PLAG1 and HMGA2. Interestingly, rearrangements of PLAG1/HMGA2 were identified in most hypocellular PAs but only in a small subset of cellular PAs. Fluorescence in situ hybridization for PLAG1 or HMGA2 can be used to distinguish between PA and CA ex-PA and their morphologic mimics.

Metastatic prostate adenocarcinoma to the penis: a series of 29 cases with predilection for ductal adenocarcinoma.

Twenty-nine men with metastatic prostate adenocarcinoma to the penis were identified at our institution between 1993 and 2013. Of the 29 patients, 19 had a prior history of adenocarcinoma of the prostate, and 8 of those had ductal features in the primary lesion. Sixteen of 29 revealed ductal features in the metastasis. Seven of the 8 cases with ductal features in the primary had ductal features in the penile metastasis. Seven penile metastases were proven to be of prostatic origin solely by immunohistochemistry. Three cases were originally misdiagnosed as urothelial carcinoma upon review of the penile lesion. Other variant morphologies in the metastases included sarcomatoid carcinoma, small cell carcinoma, and adenosquamous carcinoma. In summary, prostate carcinoma involving the penis displays ductal features considerably more often than prostate cancer in general. Features that can cause difficulty in recognizing metastatic prostate adenocarcinoma to the penis include the unusual anatomic site for prostate cancer, poor differentiation, an increased prevalence of variant morphology, a long interval from the primary lesion, and, in some cases, no documented history of a primary prostatic lesion. Immunohistochemical analysis should be performed to rule out prostate carcinoma in penile/penile urethral tumors with morphology that differs from typical squamous or urothelial carcinoma. Even in the setting of metastatic disease, there is a critical need for an accurate diagnosis so that the appropriate therapy can be initiated, symptomatic relief can be provided, and long-term survival achieved in some cases, while at the same time avoiding penectomy for a misdiagnosis of a primary penile cancer.

Heterogeneous clinicopathological features of intraductal carcinoma of the prostate: a comparison between "precursor-like" and "regular type" lesions.

Intraductal carcinoma of the prostate (IDC-P) has been described as a lesion associated with intraductal spread of invasive carcinoma and consequently aggressive disease. However, there are a few reported cases of pure IDC-P without an associated invasive component, strongly suggesting that this subset of IDC-P may represent a precursor lesion. We compared the clinicopathological features between the morphologically "regular type" IDC-P and "precursor-like" IDC-P. IDC-P was defined as follows; 1) solid/dense cribriform lesions or 2) loose cribriform/micropapillary lesions with prominent nuclear pleomorphism and/or non-focal comedonecrosis. We defined precursor-like IDC-P as follows; 1) IDC-P without adjoining invasive adenocarcinoma but carcinoma present distant from the IDC-P or 2) IDC-P having adjoining invasive microcarcinoma (less than 0.05 ml) and showing a morphologic transition from high-grade prostatic intraepithelial neoplasia (HGPIN) to the IDC-P. IDC-P lacking the features of precursor-like IDC-P was categorized as regular type IDC-P. Of 901 radical prostatectomies performed at our hospital, 141 and 14 showed regular type IDC-P and precursor-like IDC-P in whole-mounted specimens, respectively. Regular type IDC-P cases had significantly higher Gleason score, more frequent extraprostatic extension and seminal vesicle invasion, more advanced pathological T stage, and lower 5-year biochemical recurrence-free rate than precursor-like IDC-P cases. Multivariate analysis revealed nodal metastasis and the presence of regular type IDC-P as independent predictors for biochemical recurrence. Our data suggest that IDC-P may be heterogeneous with variable clinicopathological features. We also suggest that not all IDC-P cases represent intraductal spread of pre-existing invasive cancer, and a subset of IDC-P may be a precursor lesion.

ERG expression in intraductal carcinoma of the prostate: comparison with adjacent invasive prostatic adenocarcinoma.

Intraductal carcinoma of the prostate is a growth pattern of prostatic adenocarcinoma that has not been well characterized from the molecular standpoint. It remains debatable whether intraductal carcinoma of the prostate represents colonization of benign glands by pre-existing conventional prostatic adenocarcinoma, or progression of high-grade prostatic intraepithelial neoplasia. TMPRSS2-ERG is the most common gene fusion in conventional prostatic adenocarcinoma, identified in about 40-70% of cases. In this study, we compared the expression of ERG in intraductal carcinoma of the prostate and adjacent conventional prostatic adenocarcinoma. Thirty-one confirmed cases of intraductal carcinoma of the prostate, with adjacent conventional prostatic adenocarcinoma and available tissue blocks, were identified at our institution. Immunohistochemical stains were performed for ERG using a rabbit anti-ERG monoclonal antibody. The ERG expression in the intraductal carcinoma of the prostate component was compared with that in the adjacent conventional prostatic adenocarcinoma. Mean patient age was 65 years (range: 48-79 years). Positive ERG expression was identified in 11/31 (35%) cases of intraductal carcinoma of the prostate. In all 11/11 (100%) cases with positive ERG expression in the intraductal carcinoma of the prostate component, ERG expression was also positive in the adjacent conventional prostatic adenocarcinoma. In the 20/31 cases with negative ERG expression in the intraductal carcinoma of the prostate component, ERG was also negative in the adjacent conventional prostatic adenocarcinoma. It is highly conceivable that based on the identical ERG expression (positive or negative) in intraductal carcinoma of the prostate and the adjacent conventional prostatic adenocarcinoma, intraductal carcinoma of the prostate most likely represents colonization of benign glands by adjacent pre-existing conventional prostatic adenocarcinoma.

BOLD-MRI of breast invasive ductal carcinoma: correlation of R2* value and the expression of HIF-1α.

OBJECTIVE: To explore the reliability and feasibility of blood oxygenation level-dependent-based functional magnetic resonance imaging (BOLD-fMRI) to depict hypoxia in breast invasive ductal carcinoma. METHODS: A total of 103 women with 104 invasive ductal carcinomas (IDCs) underwent breast BOLD-fMRI at 3.0 T. Histological specimens were analysed for tumour size, grade, axillary lymph nodes and expression of oestrogen receptors, progesterone receptors, human epidermal growth factor receptor 2, p53, Ki-67 and hypoxia inducible factor 1α (HIF-1α). The distribution and reliability of R2* were analysed. Correlations of the R2* value with the prognostic factors and HIF-1α were respectively analysed. RESULTS: The R2* map of IDC demonstrated a relatively heterogeneous signal. The mean R2* value was (53.4 ± 18.2) Hz. The Shapiro-Wilk test (W = 0.971, P = 0.020) suggested that the sample did not follow a normal distribution. The inter-rater and intrarater correlation coefficient was 0.967 and 0.959, respectively. The R2* values of IDCs were significantly lower in patients without axillary lymph nodes metastasis. The R2* value had a weak correlation with Ki67 expression (r = 0.208, P = 0.038). The mean R2* value correlated moderately with the level of HIF-1α (r = 0.516, P = 0.000). CONCLUSION: BOLD-fMRI is a simple and non-invasive technique that yields hypoxia information on breast invasive ductal carcinomas.

Primary mammary-like ductal carcinoma of the vulva: a case report and analysis of the literature.

Mammary-like vulvar carcinoma represents an extremely rare disease. Here, the authors report a case of mammary-like ductal carcinoma of the vulva. A 71-year-old woman affected by stage T2N1M0 mammary-like vulvar carcinoma underwent neoadjuvant chemotherapy, radical vulvectomy, and adjuvant antioestrogen hormone therapy. The patient is alive, 24 months after surgery, with no clinical and radiological evidence of disease. To provide a better insight in to the clinical approach for this rare disease, a review of the available literature was performed.

Low-grade salivary duct carcinoma of the parotid gland: report of a case with immunohistochemical analysis.

Salivary duct carcinoma (SDC) is a highly aggressive malignancy of the salivary glands. However, one type of SDC, which shows minimal invasion and better prognosis, is known as low-grade SDC (LG-SDC). This report presents an additional case of LG-SDC of the parotid gland. The patient was a 38-year-old Japanese woman who noticed painless swelling of the left parotid region. Grossly, the cut surface of the tumor was cystic. Microscopically, the tumor showed a multicystic pattern, which was lined by eosinophilic to clear atypical cells with cribriform or Roman bridge patterns. An immunohistochemical examination revealed the tumor was positive for cytokeratin (CK) 7 and epithelial membrane antigen, partially positive for androgen receptor and gross cystic disease fluid protein-15, and diffusely positive for Her-2/Neu, progesterone, and estrogen receptors. The cancer cells showed focal immunopositivity for S-100 protein. Immunostaining for p63, CK14, and calponin showed an in situ pattern in most areas of this tumor, whereas the tumor showed minimal invasion. The cancer cells were diffusely positive for MUC1 and MUC6 and focally positive for MUC2 and MUC4. Finally, the tumor was diagnosed to be LG-SDC. The differential diagnosis and the mucin pattern were evaluated.

Atypical ductal adenocarcinoma of the prostate with endometrioid immunohistological features.

We present the case of a 52-year-old Caucasian male, admitted to our institution for a verumontanum adenocarcinoma, partially resected endoscopically, a month earlier at another urological clinic. The prior pathological examination wasn't able to give diagnosis. The extensive assessment by clinical workup, ultrasound, flexible cystoscopy, CT scan, and MRI revealed a prostatic tumor extending from the verumontanum to the left lobe and seminal vesicle. The patient underwent radical prostatectomy. The pathological examination revealed a ductal like adenocarcinoma, positive on immunohistochemistry for pan cytokeratin (AE1/AE3), CD10, endomysial antibody EMA and progesterone receptors (PR) and negative for prostate specific antibody (PSA), prostatic specific acid phosphatase (PSAP) and androgen receptors (AR). Ductal like adenocarcinoma of the prostate with endometrioid immunohistological features in the absence of prostate markers is an unusual condition.

Gene expression profiles of ductal versus acinar adenocarcinoma of the prostate.

Ductal adenocarcinoma is an uncommon variant of prostatic adenocarcinoma with a generally more aggressive clinical course than usual acinar adenocarcinoma. However, the molecular distinction between ductal and acinar adenocarcinomas is not well characterized. The aim of this investigation was to evaluate the relatedness of ductal versus acinar prostatic adenocarcinoma by comparative gene expression profiling. Archived, de-identified, snap frozen tumor tissue from 5 ductal adenocarcinomas, 3 mixed ductal-acinar adenocarcinomas, and 11 acinar adenocarcinomas cases were analyzed. All cases of acinar and ductal adenocarcinomas were matched by Gleason grade. RNA from whole tissue sections of the 5 ductal and 11 acinar adenocarcinomas cases were subjected to gene expression profiling on Affymetrix U133Plus2 microarrays. Independently, laser-capture microdissection was also performed on the three mixed ductal-acinar cases and five pure acinar cases to isolate homogeneous populations of ductal and acinar carcinoma cells from the same tumor. Seven of these laser-capture microdissected samples (three ductal and four acinar cell populations) were similarly analyzed on U133Plus2 arrays. Analysis of data from whole sections of ductal and acinar carcinomas identified only 25 gene transcripts whose expression was significantly and at least two-fold different between ductal and acinar adenocarcinomas. A similar analysis of microdissected cell populations identified 10 transcripts, including the prolactin receptor, with more significant differences in expression of 5- to 27-fold between ductal and acinar adenocarcinomas cells. Overexpression of prolactin receptor protein in ductal versus acinar adenocarcinoma was confirmed by immunohistochemistry in an independent set of tumors. We conclude that ductal and acinar adenocarcinomas of the prostate are strikingly similar at the level of gene expression. However, several of the genes identified in this study, including the prolactin receptor, represent targets for further investigations on the molecular basis for histomorphological and clinical behavioral differences between acinar and ductal adenocarcinomas.

Molecular imaging of the breast.

OBJECTIVE: Personalized health care centers around the concept that each tumor and its host environment is unique; optimal treatment and expected response for any given woman presenting with a newly diagnosed breast cancer differ from the care and response of other women. CONCLUSION: As more is understood about the molecular subtypes of breast cancer and as development of targeted therapies progresses, the possibility of earlier treatment response assessment and even improved detection will be realized.

Pl6 expression in Paget's disease of the breast.

BACKGROUND: Paget's disease of the nipple is generally associated with an underlying invasive cancer or an underlying ductal carcinoma in situ. Epidermotropic theory maintains that Paget's cells are derived from an underlying mammary in situ adenocarcinoma. Because p16 protein plays a major role in cell-cycle control and in tumoral cell mobility, we analyzed p16 expression in Paget's disease of the nipple and in associated underlying ductal carcinoma in situ. METHODS: The expression of p16 protein was analyzed by immunohistochemistry in eight cases of Paget's disease of the nipple with associated underlying ductal carcinoma in situ. The Student's t-test (2-tailed) was used to establish the equality of means. RESULTS: The expression of p16 protein was observed in 87.5% (7/8 cases) both in the nipple disease and in the associated underlying ductal carcinoma in situ. The difference between the two populations was not statistically significant. In normal breast tissue, no expression of the protein was observed. CONCLUSION: The positive p16 expression in Paget's disease of the nipple and the underlined ductal carcinoma in situ and its role in cell motility lead us to propose a role of p16 in the spread of this disease.