Optimal value of CA19-9 determined by KRAS-mutated circulating tumor DNA contributes to the prediction of prognosis in pancreatic cancer patients.

Despite the acceptance of carbohydrate antigen 19-9 (CA19-9) as a valuable predictor for the prognosis of pancreatic ductal adenocarcinoma (PDAC), its cutoff value remains controversial. Our previous study showed a significant correlation between CA19-9 levels and the presence of KRAS-mutated ctDNA in the blood of patients with PDAC. Based on this correlation, we investigated the optimal cutoff value of CA19-9 before surgery. Continuous CA19-9 values and KRAS-mutated ctDNAs were monitored in 22 patients with unresectable PDAC who underwent chemotherapy between 2015 and 2017. Receiver operating characteristic curve analysis identified 949.7 U/mL of CA19-9 as the cutoff value corresponding to the presence of KRAS-mutated ctDNA. The median value of CA19-9 was 221.1 U/mL. Subsequently, these values were verified for their prognostic values of recurrence-free survival (RFS) and overall survival (OS) in 60 patients who underwent surgery between 2005 and 2013. Multivariate analysis revealed that 949.7 U/mL of CA19-9 was an independent risk factor for OS and RFS in these patients (P = 0.001 and P = 0.010, respectively), along with lymph node metastasis (P = 0.008 and P = 0.017), unlike the median CA19-9 level (P = 0.150 and P = 0.210). The optimal CA19-9 level contributes to the prediction of prognosis in patients with PDAC before surgery.

Multiplatform Investigation of Plasma and Tissue Lipid Signatures of Breast Cancer Using Mass Spectrometry Tools.

Plasma and tissue from breast cancer patients are valuable for diagnostic/prognostic purposes and are accessible by multiple mass spectrometry (MS) tools. Liquid chromatography-mass spectrometry (LC-MS) and ambient mass spectrometry imaging (MSI) were shown to be robust and reproducible technologies for breast cancer diagnosis. Here, we investigated whether there is a correspondence between lipid cancer features observed by desorption electrospray ionization (DESI)-MSI in tissue and those detected by LC-MS in plasma samples. The study included 28 tissues and 20 plasma samples from 24 women with ductal breast carcinomas of both special and no special type (NST) along with 22 plasma samples from healthy women. The comparison of plasma and tissue lipid signatures revealed that each one of the studied matrices (i.e., blood or tumor) has its own specific molecular signature and the full interposition of their discriminant ions is not possible. This comparison also revealed that the molecular indicators of tissue injury, characteristic of the breast cancer tissue profile obtained by DESI-MSI, do not persist as cancer discriminators in peripheral blood even though some of them could be found in plasma samples.

Intraductal carcinoma of the prostate in prostate biopsy samples: correlation with aggressive pathological features after radical prostatectomy and prognostic value in high-risk prostate cancer.

Intraductal carcinoma of the prostate (IDC-P) is an aggressive pathological pattern of prostate cancer (PCa). We investigated the association of IDC-P in prostate biopsy (PBx) with several pathological features after radical prostatectomy (RP) and its prognostic value in high-risk PCa. A total of 418 patients with high-risk PCa after RP were included in this study. IDC-P and its architectural patterns were identified according to the 2016 World Health Organization Classification. Chi-squared test and logistic regression were used to investigate the correlation between IDC-P and post-RP pathological features. Kaplan-Meier curves and Cox regression were applied to explore the prognostic value of IDC-P. IDC-P was identified in PBx in 36/418 (8.6%) patients. Logistic regression indicated that IDC-P in PBx was independently associated with several pathological features of RP, including Gleason score 8-10 (P < 0.001), seminal vesicular invasion (P < 0.001), and pathological T (pT) 3a (P = 0.043). Patients with IDC-P in PBx manifested poorer biochemical-free survival (BFS) than those without IDC-P (37.47 months vs not reached, P < 0.001). The addition of IDC-P in several prognostic nomograms could improve the predictive accuracy of these tools. We conclude that IDC-P in PBx is positively associated with several aggressive pathological features after RP in high-risk PCa. In addition, IDC-P in PBx could effectively predict the BFS of high-risk PCa patients after RP.

Predictive factors of biochemical recurrence after radical prostatectomy for high-risk prostate cancer.

OBJECTIVE: To identify risk factors of biochemical recurrence after radical prostatectomy in high-risk patients. METHODS: A total of 191 high-risk prostate cancer patients according to the D'Amico classification treated with radical prostatectomy at a single institution between April 2000 and December 2013 were enrolled. The pathological evaluation including intraductal carcinoma of prostate was reassessed, and the clinical and pathological risk factors of biochemical recurrence were analyzed. RESULTS: The median follow up after radical prostatectomy was 49 months. The 5-year biochemical recurrence-free survival rate after radical prostatectomy in high-risk prostate cancer patients was 41.6%. Initial prostate-specific antigen, pathological Gleason score, seminal vesicle invasion, extraprostatic extension and intraductal carcinoma of the prostate were significantly associated with biochemical recurrence-free survival. The 5-year biochemical recurrence-free survival rates in patients with zero, one, two and three of these risk factors were 92.9%, 70.7%, 38.3% and 28.8%, respectively. In patients with four or more factors, the biochemical recurrence-free survival rate was 6.1% after 18 months. CONCLUSIONS: In D'Amico high-risk patients treated with radical prostatectomy, risk factors for biochemical recurrence can be identified. Patients with fewer risk factors have longer biochemical recurrence-free survival, even among these high-risk cases.

Plasma apolipoprotein A1 levels at diagnosis are independent prognostic factors in invasive ductal breast cancer.

Strong evidence exists indicating that the risk of breast cancer (BC) occurrence is influenced by complex internal environmental factors, including blood lipid and lipoprotein components. However, the roles of these components in BC development and progression remain controversial. This study examined whether serial serum lipid and lipoprotein measurements were associated with breast cancer risk and whether lipoproteins had BC prognostic properties. We compared the plasma-related parameter levels, including lipid and lipoprotein levels between 299 patients with invasive ductal breast cancer, also known as invasive ductal carcinoma (IDC), and 200 healthy donors. We performed univariate and multivariate logistic regression analyses to assess overall survival (OS) and disease-free survival (DFS). We found that the serum glucose, triacylglycerol, and low-density lipoprotein levels were significantly higher in patients with IDC than in healthy donors. However, high-density lipoprotein and apolipoprotein A1 (apoA1) levels were lower in patients with IDC than in healthy donors. Multivariate regression analysis demonstrated that elevated apoA1 levels were associated with a reduced risk of IDC, and univariate analysis showed that patients with IDC with lower apoA1 levels at diagnosis had larger tumors than patients with high apoA1 levels. Moreover, patients with IDC with lower apoA1 levels were more likely to have positive axillary lymph nodes, and were diagnosed at more advanced disease stages than patients with high apoA1 levels. We used a Cox regression model to assess the relationships between the above parameters and DFS and OS, after adjusting for tumor T and N stages, which were determined using the TNM classification system, and immunohistochemical subtypes. We found that lower apoA1 levels at diagnosis were associated with poor DFS and OS. At 60 months of follow-up, the DFS rate is 74.5% in the apoA1 L1 group, 89.9% in apoA1 L2 group, and 93.1% in apoA1 L3 group (p=0.0002). Similarly, the OS rate is 78.2% in apoA1 L1 group, 91.3% in apoA1 L2 group, and 93.7% in apoA1 L3 group (p=0.0012). In conclusion, our data indicate that low apoA1 levels are an independent predictor of the poor clinical outcomes in IDC patients.

Relationship between erb-B2 mRNA Expression in Blood and Tissue of Invasive Ductal Carcinoma Breast Cancer Patients and Clinicopathological Characteristics of the Tumors.

Molecular detection methods such as RT-PCR for detecting breast cancer-associated gene expression in the peripheral blood have the potential to modify breast cancer (BC) staging and therapy. In this regard, we evaluated the potential of erb-B2 molecular marker in BC detection and analyzed the expression of erb-B2 mRNA in the peripheral blood and fresh tissue samples of 50 pretreated female BC patients and 50 healthy females by reverse transcription-PCR (RT-PCR) method. We also assessed the correlation of erb-B2 mRNA marker positivity in peripheral blood and tumor tissue samples with clinical and pathological factors in BC patients in order to evaluate its prognostic value. It was shown that there is a significant difference between healthy females and BC patients with expression of the erb-B2 molecular marker (p<0.01). A significant difference between the expression of erb-B2 in the peripheral blood and tissue samples of BC patients (p<0.01) and the frequency of circulating erb-B2 mRNA expression in peripheral blood and in tissue was detected by RT-PCR. No correlation was found between erb-B2 mRNA expression in blood or tumor tissue samples and lymph node, tumor grade, tumor stage, tumor size, patient's age, ki67, estrogen receptor (ER), progesterone receptor (PGR), P53, and HER-2 status. However, in a small subset of 31 BC patients we found that expression of erb-B2 in peripheral blood or in both peripheral blood and tumor tissue was directly correlated with lympho-vascular invasion and perineural invasion as poor prognostic features. The highest rates of erb-B2 expression in peripheral blood or tumor tissue were in the ER and PR negative and HER-2 positive group. This study suggests that the application of the RT-PCR and immunohistochemical methods for erb-B2 molecular marker detection would provide a higher detection rate, especially in early stage BC.

Invasive Ductal Carcinoma in a 46,XY Partial Androgen Insensitivity Syndrome Patient on Hormone Therapy.

BACKGROUND: The hormonal management of patients with androgen insensitivity can be challenging. CASE: An illustrative case is presented of a newborn with ambiguous genitalia who was raised female. She was diagnosed as 46,XY Disorder of Sexual Development with partial androgen insensitivity. To induce puberty, conjugated equine estrogens were administered beginning at age 12. At age 13, she instead began taking combined oral contraceptives for maternal concerns about height and continued taking them for social reasons. Invasive ductal carcinoma was diagnosed at age 27, and the patient was treated with chemotherapy, radiation therapy, bilateral mastectomies, and endocrine therapy. SUMMARY AND CONCLUSION: The current literature is reviewed, and hormonal management and other risks for breast cancer are discussed.

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.

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.

Upregulation of human leukocyte antigen-G expression and its clinical significance in ductal breast cancer.

Human leukocyte antigen(HLA)-G could inhibit functions of immune cells and induce regulatory T cells (Treg) and could be involved in antitumor immune responses. In the current study, HLA-G expression in 58 primary breast cancer lesions was analyzed with immunohistochemistry. Plasma soluble HLA-G was detected with enzyme-linked immunosorbent assay in 92 breast cancer patients and in 70 normal healthy donors. The proportion of CD4(+)CD25(+)FoxP3(+) Treg was analyzed with flow cytometry in 64 breast cancer patients and 23 normal controls. HLA-G expression was observed in 70.7% (41/58) of breast cancer lesions. Lesion HLA-G expression was more frequently observed in advanced disease stage (I/II vs III/IV, p = 0.044) and tumor grade (I/II vs III/IV, p = 0.021). sHLA-G was dramatically increased in patients when compared with normal controls (median 82.19 vs 9.65 U/ml, p < 0.001); The area under the receiver operating characteristic (ROC) curve for sHLA-G was 0.953 (95% confidence interval [CI] = 0.926-0.981, p < 0.001). However, sHLA-G was irrelevant to the disease stage and tumor grade. Moreover, CD4(+)CD25(+)FoxP3(+) Treg are markedly increased in the breast cancer patients compared with normal controls (4.46+/-1.36% vs 2.67+/-1.45%, p < 0.001), and the increased frequency of Treg was strongly correlated to sHLA-G levels (R = 0.582, p = 0.001). Our findings indicated that HLA-G could play critical roles in the progression of breast cancer, and plasma sHLA-G levels might be a useful preoperative biomarker for diagnosis.

Circulating soluble CTLA4 (sCTLA4) is elevated in patients with breast cancer.

Soluble CTLA4 (sCTLA4) was assessed in sera of 43 new cases with breast cancer and 44 age- and sex-matched healthy individuals by enzyme-linked immunosorbent assay method. Associations of sCTLA4 levels with the six important CTLA4 Single Nucleotide Polymorphisms (SNPs) and with the resulted haplotypes were investigated. Results revealed significant concentration of sCTLA4 in patients with breast cancer (23.5 ± 14.96 versus 7.69 ± 4.04 ng/ml, p < .001). Patients' sCTLA4 concentration observed to be affected by the SNPs at positions +49 and +1822 and haplotype combination TACACA/TACGTG. These findings suggest that increased sCTLA4 may contribute in CTLA4-induced suppression of tumor immunity and provide explanations for the widely reported association of CTLA4 gene with cancer.

Next generation sequencing of serum circulating nucleic acids from patients with invasive ductal breast cancer reveals differences to healthy and nonmalignant controls.

Circulating nucleic acids (CNA) isolated from serum or plasma are increasingly recognized as biomarkers for cancers. Recently developed next generation sequencing provides high numbers of DNA sequences to detect the trace amounts of unique serum biomarkers associated with breast carcinoma. Serum CNA of 38 women with ductal carcinoma was extracted and sequenced on a 454/Roche high-throughput GS-FLX platform and compared with healthy controls and patients with other medical conditions. Repetitive elements present in CNA were detected and classified, and each repetitive element was normalized based on total sequence count or repeat count. Multivariate regression models were calculated using an information-theoretical approach and multimodel inference. A total of 423,150 and 953,545 sequences for the cancer patients and controls, respectively, were obtained. Data from 26 patients with stages II to IV tumors and from 67 apparently healthy female controls were used as the training data set. Using a bootstrap method to avoid sampling bias, a five-parameter model was developed. When this model was applied to a validation data set consisting of patients with tumor stage I (n = 10) compared with healthy and nonmalignant disease controls (n = 87; 1,261,561 sequences) a sensitivity of 70% at a specificity of 100% was obtained. At a diagnostic specificity level of 95%, a sensitivity of 90% was calculated. Identification of specific breast cancer-related CNA sequences provides the basis for the development of a serum-based routine laboratory test for breast cancer screening and monitoring.

Any proportion of ductal adenocarcinoma in radical prostatectomy specimens predicts extraprostatic extension.

Ductal adenocarcinoma of the prostate is an aggressive malignancy, often presenting at an advanced stage. In mixed ductal and acinar adenocarcinomas, the relationship between the proportion of the ductal component of the tumor and the pathologic stage and whether or not aggressive behavior is simply a function of grade remains undetermined. From 268 consecutive radical prostatectomies undertaken as a curative procedure for clinical localized prostate cancer, we identified 34 cases (12.7%) with ductal adenocarcinoma of the prostate comprising 5% to 100% of the total tumor volume. For cases with a ductal adenocarcinoma of the prostate component, the mean age at diagnosis of 60 years (range 49-69 years), mean serum prostate-specific antigen of 8.4 ng/mL (range, 0.8-21 ng/mL) and positive surgical margin rate of 17.6% did not differ significantly from that of the pure adenocarcinoma group. All 34 patients with ductal adenocarcinoma of the prostate had peripheral zone involvement while 16 (46%) also had transition zone involvement. Twenty-five (73%) cases with ductal adenocarcinoma of the prostate had extraprostatic extension (pT3), which compared to 32.9% with acinar adenocarcinoma. The presence of ductal adenocarcinoma of the prostate (P < .0001), high tumor volume (P = .001) and Gleason score >7 (P = .04) significantly predicted pT3 staging category, and the presence of ductal adenocarcinoma of the prostate remained a significant predictor for pT3, after adjusting for tumor volume and Gleason score >7. The proportion of ductal adenocarcinoma of the prostate did not significantly modify the strength of the observed association with pathological stage. In view of the significant association with extraprostatic extension we would recommend that in both core biopsies and radical prostatectomy specimens any proportion of ductal adenocarcinoma of the prostate should be reported.

Ductal adenocarcinoma of the prostate diagnosed on transurethral biopsy or resection is not always indicative of aggressive disease: implications for clinical management.

OBJECTIVE: To report the clinicopathological characteristics of 23 cases of ductal adenocarcinoma of the prostate (DCP) and discuss the implications for clinical management, as DCP is considered an aggressive subtype of prostate adenocarcinoma (PA). PATIENTS AND METHODS: The presence of DCP in transrectal ultrasonography-guided prostate biopsy (TRUSB) is associated with adverse pathological findings at radical prostatectomy (RP) and clinical outcomes, and the significance of detecting DCP initially in transurethral biopsy (UB) or transurethral resection (TURP) in the present era of screening with prostate-specific antigen (PSA) is unclear. The study included 23 cases of pure DCP without acinar PA diagnosed on UB or TURP. Demographic information, serum PSA level, follow-up surgical procedures (RP, TURP or TRUSB) and outcome data were collected. RESULTS: The mean age of the men was 67.5 years and the mean PSA level before the procedure was 12.5 ng/mL; 14 cases were detected on UB and nine were diagnosed on TURP. The mean (range) follow-up was 4 (1-23) months after the initial procedure. In all, 21 (89%) patients had DCP or PA in follow-up procedures. Two (11%) patients had no residual cancer, one on RP and the other on two repeat TURPs. DCP or PA was found in 12 RP cases; four patients had Gleason score 7 PA, three of which were organ-confined, and eight had Gleason score > or = 8 PA. Extraprostatic extension, seminal vesicle invasion and regional lymph node metastasis were present in seven, six and two cases, respectively. CONCLUSIONS: Most DCP diagnosed on UB or TURP in this contemporary series was associated with aggressive PA, but a subset presented as a small periurethral tumour with no concomitant acinar PA, and was eradicated by the initial biopsy/TURP alone. We recommend that patients with a diagnosis of DCP on UB or TURP undergo follow-up TURP and TRUSB before radical surgery is offered.

[Expression of B7-H1 protein in human pancreatic carcinoma tissues and its clinical significance].

BACKGROUND AND OBJECTIVE: B7-H1, a member of B7 family, is expressed in tumor cells and has emerged as an important immune modulator capable of suppressing host immunity by inhibiting T cells function. This study was to probe into the correlation between the expression level of B7-H1 protein in pancreatic carcinoma tissues and clinicopathological characteristics and prognosis. METHODS: The expression of B7-H1 was measured in 40 cases of pancreatic carcinoma tissues and 10 cases of normal corresponding paracarcinoma tissues by immunohistochemistry. The relationship between the expression level of B7-H1 and clinicopathological characteristics and survival was analyzed. RESULTS: The positive rate of B7-H1 was significantly higher in the tumor tissues [45.00% (18/40)] than in the normal corresponding paracarcinoma tissues [0(0/10)] (P<0.05); moreover, B7-H1 expression was significantly associated with the staging of tumor and preoperative serum CA19-9 level (P<0.05). The multivariate cox proportional hazards regression analysis of prognostic factors for overall survival and relapse-free survival showed that the expression of B7-H1 was an independent factor for poor prognosis. CONCLUSION: B7-H1 protein was expressed in human pancreatic carcinoma tissues, and was associated with the prognosis.

Proteomics-based identification of alpha1-antitrypsin and haptoglobin precursors as novel serum markers in infiltrating ductal breast carcinomas.

BACKGROUND: The identification of pathological markers of breast cancer for either diagnosis, treatment response or for survival is of critical importance. METHODS: Serum protein profiling using 2-DE separations coupled to matrix-assisted laser desorption ionization mass spectrometry has been used to explore protein alterations in patients with infiltrating ductal breast carcinomas (IDCA). Sera from 39 breast cancer patients and 40 healthy controls were selected for screening study using 2-DE combined with MS. The protein expression patterns obtained after the depletion of high abundance proteins was determined by coomassie blue G-250 stain after 2-DE electrophoresis. RESULTS: Six proteins that expressed differentially in the IDCA group were found. The expression levels of four isoforms corresponding to haptoglobin precursor and two isoforms of alpha1-antitrypsin precursor (alpha1-AT) were upregulated in sera from breast cancer patients. There was an increased expression of both proteins in the sera of patients with various tumor stages (I, II, III) in comparison to healthy women. Applying immunohistochemistry, we further validated alpha1-AT immunoreactivity in 51 formalin-fixed paraffin-embedded sections of breast tumors. Enhanced expression of alpha1-AT like activity has been found in IDCA breast tumors, as well as, in different histological types of breast cancer. No significant association has been found with lymph node occurrence, while in high tumor categories a tendency to an increased expression of alpha1-AT has been found, thereby suggesting a possible role of this protein in tumor growth. CONCLUSIONS: These proteins may constitute new and useful markers of breast cancer that offer a clue to a better understanding of inflammatory pathways and carcinogenesis events linked to breast cancer progression.

Elevated free IGF2 levels in localized, early-stage breast cancer in women.

OBJECTIVE: Epidemiological studies imply an association between circulating IGF1 and breast cancer, whereas the role of IGF2, which also acts on the IGF1 receptor, is less settled. This study investigates the association between IGF2 and breast cancer in patients with localized disease. DESIGN: The participants were women with well-characterized, early stage, localized breast cancer (n=43) and matched healthy women (n=38), from whom fasting serum levels of IGF-related peptides were measured. RESULTS: In patients, mean free IGF2 was increased (+57%, P<0.001), in spite of reduced total IGF2 levels (-12%, P=0.003) when compared with controls. Similar changes were seen in free IGF1 (+28%, P=0.004) and total IGF1 (-16% P=NS). Pro-IGF2 and IGF-binding protein 1 (IGFBP1) were unchanged. IGFBP2 was reduced by 22% in the patients (P=0.004). The patients showed reduced IGFBP3 protease activity and accordingly increased levels of intact IGFBP3, whereas total IGFBP3 was unchanged. CONCLUSION: Women with localized, early-stage breast cancer show elevated circulating free IGF1 and IGF2, reduced total IGF2 and alterations in IGFBPs. The changes observed despite minimal cancer disease suggest a role for the circulating IGF system in the progression of breast cancer in women.

High-grade prostatic intraepithelial neoplasialike ductal adenocarcinoma of the prostate: a clinicopathologic study of 28 cases.

Most of the prostatic ductal adenocarcinomas of the prostate are characterized by cribriform and/or papillary architecture lined by columnar pseudostratified malignant epithelium. We report 28 cases of ductal adenocarcinomas on needle biopsy and transurethral resection of prostate closely resembling high-grade prostatic intraepithelial neoplasia (HGPIN) composed of simple glands with flat, tufting, or micropapillary architecture. The mean age of the patients was 68 years (range, 50 to 91 y). Prostate specific antigen serum level at diagnosis ranged from 1.2 to 12.1 ng/mL. Treatment included radical prostatectomy (n=9), hormone therapy (n=7), radiotherapy (n=5), and cryotherapy (n=1). Three patients had recent biopsies without information on treatment and 3 patients were lost to follow-up after diagnosis. The number of cores involved by tumor in each case ranged from 1 to 18, with more than 1 core involved in 13 cases. Flat was the most common pattern (42%), followed by tufted (41%), and micropapillary (17%) (some with more than 1 pattern). Fourteen cases revealed segments of dilated gland on the edge of the biopsies, suggesting a large gland component. In radical prostatectomies, tumor was primarily composed of small (25%), medium (17%), or cystically dilated (58%) cancer glands, with all cases demonstrating a mixture of different gland sizes. Cytologically, tumors were characterized by tall columnar atypical cells, basally located nuclei, and amphophilic cytoplasm. The tumors lacked marked pleomorphism, necrosis, solid areas, cribriform formation, or true papillary fronds. Immunohistochemically, alpha-methyl acyl coenzyme-A racemase staining was seen in 93% of cases, with the majority showing strong and diffuse staining. No basal cells were present on p63 and/or high molecular weight cytokeratin staining. In the radical prostatectomy specimens, tumor volumes ranged from a small focus (less than 0.01 cm3) to 1.2 cm3. Concurrent conventional acinar Gleason score 6 adenocarcinomas were seen in 6 of the 9 radical prostatectomy cases, in all cases as separate nodules from the PIN-like ductal adenocarcinomas. Only one of the PIN-like ductal adenocarcinomas at radical prostatectomy had extraprostatic extension, which was focal. PIN-like ductal adenocarcinoma differs from HGPIN by the presence of cystically dilated glands, a greater predominance of flat architecture, and less frequently prominent nucleoli. Verification often requires the immunohistochemical documentation of the absence of basal cells in numerous atypical glands. Although usual ductal adenocarcinoma is considered comparable to Gleason score 8, PIN-like ductal adenocarcinoma was accompanied by Gleason score 6 acinar carcinoma and behaved similar to Gleason score 6 acinar cancer. Recognition of this entity is critical to differentiate it from both HGPIN and conventional ductal adenocarcinoma.