The clinical and pathological differences in prevalent round screen-detected and symptomatic invasive breast cancer

The potential benefits of breast cancer screening include the detection of cancers at a more favourable stage, however, cancers detected during the prevalent round of screening may differ from true screen-detected cancers. These differences are poorly defined. This study prospectively assessed all women between 50 and 64 years of age undergoing curative surgery for breast cancer, both screen-detected and symptomatic, in one screening centre during the prevalent round of the national breast cancer-screening programme. Four hundred and thirty seven patients (364 screen-detected and 73 symptomatic patients) underwent surgery for breast cancer. Symptomatic breast cancers were of a higher grade (p < 0.0001; Chi2) and less likely to be oestrogen receptor positive (49% versus 88%; p < 0.0001; Fisher's exact test); however there was no difference in size of tumour or axillary nodal positivity. This study suggests that tumours detected by screening during the prevalent round of a screening programme are of a more prognostically favourable type than symptomatic breast cancers in the same age group.     

Prevalence of thyroid cancer at a medical screening center: pathological features of screen-detected thyroid carcinomas

Purpose

To assess the incidence of thyroid malignancy in an adult population screened by high-resolution ultrasonography at a medical screening center and to compare the clinical and pathological features of screen-detected thyroid carcinomas to symptomatic overt thyroid carcinomas.

Materials and Methods

We calculated the prevalence of screen-detected thyroid cancer at a medical screening center using high-resolution ultrasonography and fine needle aspiration. We then compared the clinical and pathological features of screen-detected thyroid cancers (n = 46) to clinical symptomatic thyroid cancers (n = 157). We evaluated age, gender, size, perithyroidal extension, lymphovascular extension, stage, histological lymph node metastasis, and the type of cancer. We also compared the above findings of micropapillary carcinomas to papillary thyroid carcinomas that were larger than 1 cm in diameter.

Results

Screen-detected thyroid nodule patients were 2,747 (37%) of 7,491 patients. Nodules selected for fine needle aspiration were 658 and cytology confirmed malignancy were 79 (12%) nodules. When screen-detected thyroid cancers (n = 46) were compared to symptomatic overt thyroid cancers (n = 157), only statistically significant factor was size (p = 0.002). Papillary thyroid carcinomas that were larger than 1 cm had more frequent capsular invasion (p = 0.000) and a higher stage (p = 0.027), and a higher prevalence of lymph node metastases (p = 0.002).

Conclusion

Screen-detected thyroid cancers should be managed as same as symptomatic thyroid cancers in respect to size, and an assessment should strictly be based on the ultrasound features and fine needle aspiration biopsy findings.     

Mammary mucinous lesions: congeners, prevalence and important pathological associations

A retrospective histopathological study was undertaken to determine the prevalence of mucin filled ducts and their associated mucinous proliferation in 962 breast cancers and 335 benign lesions. A total of 38 (3%) cases with mucin filled ducts was identified and 27 (2%) of these showed mucin extravasation into the adjacent stroma, changes characteristic of mucocoele-like lesions. This constitutes the largest series reported to date. Of the mucocoele-like lesions 12 were prototypic screen-detected cases; 11 of which were mammographically detected on account of suspicious microcalcification and eight cases (67%) exhibited mucinous atypical ductal hyperplasia without overt malignancy. A further 12 mucocoele-like lesions were incidental findings in screen-detected (11) and symptomatic (one) cancers, the majority of which were invasive ductal carcinomas of no special type. In six of these cases (50%), mucinous atypical ductal hyperplasia or ductal carcinoma in situ was present. Thirty mucinous carcinomas constituted 3% of all cancers and three cases had associated mucocoele-like lesions. Mucinous atypical ductal hyperplasia or ductal carcinoma in situ was also associated with 11 cases of mucinous carcinoma. In six mucinous carcinomas, amorphous microcalcification with a similar appearance to that of benign mucocoele-like lesions was identified in the mucin, suggesting a possible link between the two lesions. Mucin-filled ducts or mucocoele-like lesions were almost twice as frequent in screen-detected as in symptomatic lesions. The presence of mucinous atypical ductal hyperplasia in screen-detected mucocoele-like lesions, a decade earlier than the peak of mucinous carcinoma, is a possible risk factor for subsequent invasive malignancy. Mucin-filled ducts, mucocoele-like lesions, mucinous atypical ductal hyperplasia or ductal carcinoma in situ and mucinous carcinoma may represent different stages of the same disease process. Our findings suggest that patients with mucin-filled ducts of mucocoele-like lesions merit close follow-up.     

Biological markers in human breast carcinoma

An indirect immunoperoxidase method has been used to study a series of breast carcinomas for the presence of five potential biological markers (two appropriate to breast, two placental proteins and one oncofetal protein). One or more markers were detectable in 84 per cent, of tumours, two or more in 60 per cent, and three or more in 32 per cent. Similarity of staining patterns was noted for two placental proteins and for the oncofetal protein and one placental protein. Markers appropriate to breast tissue tended to be detected in separate areas. In certain instances more than one antigen could be detected within the same cell. The relationship of the number of markers present to histological differentiation was found to be complex, but carcinomas with three or more antigens demonstrated showed a tendency to be well or moderately differ entiated. Tumours with no markers often had not metastasised to lymph nodes but conversely those with four and five markers had. A striking feature throughout the study was the heterogenous secretory nature of breast carcinomas.     

Bone metastasis is strongly associated with estrogen receptor-positive/progesterone receptor-negative breast carcinomas

Bone is one of the most common sites of distant metastasis for breast carcinomas. In this study, our objective is to identify molecular markers and molecular subtypes that may predict patients at higher risk of developing bone metastasis. Immunohistochemical analysis with antibodies against estrogen receptor α, progesterone receptor, androgen receptor, Her2/neu, epidermal growth factor receptor, CK5/6, CK14, CK17, CK8, and CK18 was performed on representative sections of 21 breast carcinomas with bone metastasis and 94 cases without bone metastasis. The expression rates of receptors, subtype distributions (basal versus nonbasal) of 3 molecular classifications (cytokeratin, triple negative, and cytokeratin/triple negative), and 5 subtypes of cytokeratin/triple negative classification were compared between these 2 groups. We found that (1) the breast cancers with bone metastasis were associated with a significant percentage of estrogen receptor–positive/progesterone receptor–negative tumors compared with tumors without bone metastasis (38% versus 6%, P < .0001). (2) There was significant difference on estrogen receptor expression between high grade and non–high grade in tumors with or without bone metastasis (P = .0084 and 1.0000, respectively). (3) The breast cancers with bone metastasis were more likely to be estrogen receptor positive (85%) and androgen receptor positive (95%) compared with those without bone metastasis (59% and 74%, respectively, both P < .05). (4) There was no significant difference between tumors with or without bone metastasis in subtype distribution (basal versus nonbasal) among all 3 molecular classifications. (5) Luminal B carcinomas of cytokeratin/triple negative classification tended to be associated with bone metastasis but not to a statistically significant extent. In conclusion, bone metastasis is strongly associated with estrogen receptor–positive/progesterone receptor–negative tumors. Significant difference in estrogen receptor expression between high-grade and non–high-grade tumors with bone metastasis suggests that different panels of molecular markers should be used to predict bone metastasis in these 2 groups of tumors.     

Oestrogen receptor, progesterone receptor, pS2, ERD5, HSP27 and cathepsin D in invasive ductal breast carcinomas

Hormonal receptors and markers for prognostic evaluation were detected immunohistochemically in 196 infiltrating ductal breast carcinomas. Immunohistochemical detection of progesterone and oestrogen receptor is a method giving results generally concordant with those of the binding assay. However, immunohistochemical detection seems better. It allows the detection of hormonal receptors on small carcinomas, it is not modified by the endogenous hormones, and it has a slightly better correlation with prognosis and with the response to hormone therapy. Immunohistochemical detection of progesterone receptor has a prognostic value, sorting a negative subgroup with a poor prognosis from the oestrogen receptor positive tumours. These results can be obtained without quantitative immunohistological methods. ERD5, pS2, HSP27 and cathepsin D are associated with oestrogen receptor positivity. pS2 and HSP27 are interesting markers. They characterize a subgroup of oestrogen receptor negative tumours with a good prognosis. Moreover, pS2 is a marker of response to hormone therapy. ERD5 and cathepsin D do not appear to be of value as markers of prognosis.     

The site of infection and ethnicity of the patient influence the biological pathways to HPV-induced mucosal cancer.

High-risk human papillomaviruses are the causative agents of cervical cancer and are also believed to be aetiologically involved in a subset of squamous cell carcinomas of the head and neck region, especially the tonsil. Cervical cancers arise through disruption of the pathways of p53 and the product of the retinoblastoma gene by the human papillomavirus oncoproteins E6 and E7. It is generally assumed that the same pathways are involved in human papillomavirus-induced carcinogenesis at other mucosal surfaces. However, the patterns of expression of cell cycle proteins targeted by human papillomavirus E6 and E7 in cancers from different anatomic sites have been inconsistent, due to either biologic or technological factors. In this study, 73 human papillomavirus, 16-positive cervical squamous cell carcinomas (35 from Australian and 38 from Chinese women) were analysed for the expression of p53, pRb, p16(INK4A), p21(CIP1/WAF1), p27(KIP1) and cyclin D1 by semiquantitative immunohistochemistry. Cervical cancers from Chinese women were found to be significantly more likely to overexpress p53, pRb, p21 and p27 than their Australian counterparts. These findings were compared with those from 31 human papillomavirus 16-positive tonsillar squamous cell carcinomas, all of Australian origin, tested using the same methodology. Comparisons of the tonsillar and combined cervical data showed that tonsillar cancers were significantly more likely to be p53-positive, whereas cervical cancers were significantly more likely to overexpress pRb, p16 and p27. When the tonsillar data were compared with cervical data from Australian women, the associations for p53 and pRb remained. These findings represent new evidence that the molecular pathways to human papillomavirus-induced mucosal cancer may be influenced by anatomic location and ethnicity.     

Microsatellite instability in sporadic mucinous colorectal carcinomas: relationship to clinico-pathological variables

A series of 44 sporadic mucinous colorectal carcinomas was analysed for microsatellite instability; 30 consecutive sporadic non-mucinous colorectal cancers served as controls. Mucinous carcinomas showed microsatellite instability more frequently than non-mucinous cancers: 26/44 and 8/30, respectively (P=0·005); the difference was higher for cancers with two or more microsatellite alterations: 12 of the 44 mucinous carcinomas versus one of the 30 non-mucinous carcinomas (P=0·007). On comparing the clinico-pathological features of mucinous carcinomas with and without microsatellite instabilities, no differences were found with respect to the following variables: sex ratio, tumour localization, tumour size, peritumoural lymphocytic infiltration, Crohn's-like lymphoid reaction, peritumoural fibrosis, Dukes' stage, and relationship with adenoma. Mucinous cancers with DNA replication errors were characterized by three features: onset in younger patients (P<0·05); exophytic gross shape (P=0·03); and an expanding pattern of growth (P=0·003). Of the 12 mucinous carcinomas with instability in two or more microsatellites, ten (83·3 per cent) exhibited an expanding pattern of growth, while mucinous cancers with instability in one microsatellite or without genomic instability showed no distinctive growth pattern. This study confirms the relationship between microsatellite instabilities and mucin production in colorectal carcinomas, but shows that replication error RER-positive and RER-negative mucinous cancers differ in few clinico-pathological features. These differences are only in part similar to those previously reported in RER-positive colorectal carcinomas. These data indicate that mucinous carcinoma of the large bowel could represent a histological subset separate from other histotypes. © 1997 John Wiley & Sons, Ltd.     

MICROSATELLITE INSTABILITY IN INTESTINAL- AND DIFFUSE-TYPE GASTRIC CARCINOMA

To investigate the role of genetic instability in the development of intestinal- and diffuse-type gastric cancers, six microsatellite loci were analysed in 98 carcinomas of the two main histotypes, at both early and advanced stages of progression, and in five preneoplastic lesions. RER+ phenotype frequency proved to be significantly higher ( P =0·013) in intestinal (23 per cent) than in diffuse cancers (5 per cent) and slightly higher in advanced (19 per cent) than in early (12 per cent) tumours. When comparing early and advanced tumours of the same histotype, a similar frequency was found for diffuse tumours (4 per cent vs. 6 per cent), and an increase from 19 to 30 per cent for intestinal cancers. Instability at more than one locus was limited to intestinal tumours and replication errors were also detected in an intestinal dysplasia. On the whole, these data suggest that genetic instability has an important and early role in gastric carcinogenesis of the intestinal type and a less important role in gastric carcinogenesis of the diffuse type. Most tumours of this panel had previously been characterized for p53 gene mutations. p53 screening was extended to all samples, to investigate the possible association between gene mutations and microsatellite instability. Analysis showed a trend ( P =0·07, Fisher's exact test) towards a negative association between these two genetic lesions in tumours of the intestinal type. © 1997 John Wiley & Sons, Ltd.     

A study of interval breast cancer within the NHS breast screening programme

AIM: To define the biological nature and malignant potential of interval cancers presenting to a breast unit within the NHS breast screening programme. METHODS: 112 interval cancers were compared with matched, screen detected and symptomatic cancers in terms of their radiographic, histopathological, and immunohistochemical features. RESULTS: Interval cancers, strictly defined, showed no characteristic radiographic pattern. In terms of size, vascular invasion, lymph node status, and prognosis they were intermediate between screen detected and symptomatic cancers. Within the interval cancers there was an excess of grade 1 and grade 3 tumours, and lesions with a high Ki67 index but immunohistochemistry otherwise failed to discriminate between the three groups. Inclusion of data from false negative "interval cancers" did not significantly alter the results. CONCLUSIONS: Interval cancers are more aggressive than screen detected cancers but in general less aggressive than symptomatic cancers. However, within a heterogeneous group, occasional interval cancers are exceptionally malignant.     

Loss of E-cadherin expression associated with lymph node metastases in small breast carcinomas

The National Breast Screening Programme affords the opportunity to study breast carcinomas at an early stage in their development. E-cadherin is a calcium-dependent, intercellular adhesion molecule whose loss of expression may facilitate the processes of invasion and metastasis of some human tumours. From a group of screen-detected ductal carcinomas less than or equal to 10 mm in diameter, 16 with lymph node metstastasis were identified and matched for grade, size and patient age with node negative tumours. The level of expression of E-cadherin (detected by immunocytochemistry) was compared in the matched pairs using a simple semi-quantitative intensity distribution scoring system. The results showed a significant (P = 0.05 Wilcoxon paired rank test) reduction of E-cadherin expression in tumours with lymph node metastases compared to those without. In the context of the small size of these tumours it is proposed that these results support the hypothesis that reduction in E-cadherin expression is an early event in the development of metastases.     

Immunohistochemical characteristics of colorectal carcinoma with DNA replication errors.

It has recently been shown that nearly all cancers from hereditary nonpolyposis colorectal cancer syndrome (HNPCC), as well as a subset of sporadic colorectal cancers, have DNA replication errors (RER) at repeated sequences distributed throughout their genome. These RER-positive cancers had pathological characteristics of more frequent exophytic growth, large size and poor differentiation. However, the histogenesis and immunohistochemical characteristics of these RER-positive cancers are not known. The poorly differentiated colorectal carcinomas are heterogenous group of neoplasms that differ in their histologic appearance and prognosis. We therefore examined RER from 69 sporadic colorectal carcinomas of poor differentiation and detected in 23 cases (33%). The pathological features of RER-positive cancers differed from those without RER. The RER-positive cancers had marked preponderance of proximal location (16/23, 70%, vs. 20/46, 43%, p < 0.04), no glandular differentiation with intense peritumoral immune response (12/23, 52% vs. 6/46, 13%, p < 0.001). Immunohistochemically, most of the RER-positive cancers were reactive for cytokeratin (22/23, 96%) and CEA (17/23, 74%), and negative for NSE (2/23, 9%), chromogranin (3/23, 13%) and synaptophysin (0/23, 0%). In comparison to 46 RER-negative tumors, RER-positive cancer had less frequent CEA expression (17/23, 74% vs. 44/46, 96%, p = 0.01). We conclude that the RER-positive colorectal carcinomas have histologic characteristics of predominantly solid, poorly differentiated adenocarcinomas with intense peritumoral reaction and the tumors should be distinguished from neuroendocrine carcinomas and other more aggressive non-glandular tumors of the colon.     

Morphology and microsatellite instability in sporadic serrated and non-serrated colorectal cancer

Colorectal serrated adenocarcinoma originates from serrated adenoma, but definite histological criteria have not yet been established. It presents with frequent DNA microsatellite instability (MSI), but the frequency of low-level (MSI-L) and high-level MSI (MSI-H) and the expression of mismatch-repair (MMR) enzymes in serrated adenocarcinoma are not known. To address these questions, morphological criteria for serrated cancers were established, their validity was tested, and MSI analysis was performed with NIH consensus markers and MMR enzyme immunohistochemistry for hMLH1, hMSH2, and hMSH6 in 35 serrated and 75 non-serrated colorectal carcinomas. Serrated carcinomas frequently showed a serrated, mucinous or trabecular growth pattern; abundant eosinophilic cytoplasm; chromatin condensation; preserved polarity; and the absence of necrosis. With these features, it was possible to distinguish them from non-serrated cancers, with the mean kappa score for five observers being 0.509. MSI analysis was successful in 31 serrated and 73 non-serrated carcinomas. 54.8% of serrated carcinomas were microsatellite-stable (MSS), 29.0% presented with MSI-L, and 16.1% presented with MSI-H, whereas 78.1% of non-serrated carcinomas were MSS, 13.7% were MSI-L, and 8.2% were MSI-H. MSI-L was more common in serrated cancers (p=0.035) and it was associated with patchy immunohistochemical staining (33.3%) of MLH1. MSI-H did not differ between serrated and non-serrated cancers (p=0.14). These results suggest that the biological background of serrated carcinomas differs from sporadic non-serrated colorectal cancer, but is not directly related to MSI.     

叶酸受体α在卵巢上皮性肿瘤中的表达

目的 探讨卵巢上皮性肿瘤中叶酸受体(FR)α的表达及其临床病理学意义.方法 制备包括86例卵巢癌及29例卵巢交界性肿瘤的组织芯片,采用免疫组织化学EnVision法检测上述肿瘤组织中FRα的表达情况,同时采用即时PCR检测40例新鲜冷冻卵巢癌组织以及14例卵巢交界性肿瘤组织中FRα mRNA的表达情况.分析卵巢上皮性肿瘤中FRα表达水平与肿瘤的组织类型、不同发病模式以及临床分期的关系.结果 免疫组织化学染色结果显示,86例卵巢癌中有40例(46.5%)对FRα呈明确阳性反应,其中浆液性癌阳性表达率最高,为62.7%(32/51),高于其他组织类型的癌(P=0.000).按照卵巢癌发病模式区分,Ⅱ型卵巢癌FRα的表达明显高于Ⅰ型卵巢癌,差异具有统计学意义(P=0.001).卵巢癌组FRα表达阳性率高于交界性肿瘤(46.5%∶27.6%),但差异无统计学意义(P=0.074).卵巢癌组FRα的表达与临床分期无相关性(P=0.498).相似的结果也见于采用即时PCR检测FRα mRNA的表达情况:卵巢癌组FRα mRNA表达值高于交界性肿瘤组(P=0.000),在交界性肿瘤中,浆液型mRNA表达值高于黏液型,差异具有统计学意义(P=0.007).结论 卵巢上皮性肿瘤中FRα呈高表达,特别是在恶性肿瘤和浆液性肿瘤中.     

Bcl-2 protein expression in lung cancer and close correlation with neuroendocrine differentiation.

For determination of the cellular distribution of bcl-2 expression in lung cancer and clarification of its correlation with cell neuroendocrine differentiation, Bcl-2 immunostaining was carried out on a large series of formalin-fixed, paraffin-embedded lung cancer samples, and four general neuroendocrine marker and seven peptide hormone stainings were carried out on all Bcl-2-positive squamous cell carcinomas and adenocarcinomas of the lung as well as on 8 pulmonary neuroendocrine carcinomas histologically diagnosed. In addition, 3 small cell lung cancer cell lines were studied by Western blotting. Neuroendocrine differentiation in Bcl-2-negative squamous cell carcinomas and adenocarcinomas was examined with chromogranin A and alpha-subunit of Go protein stainings. Bcl-2 protein was detected in 104/111 small cell carcinomas, 8/8 neuroendocrine carcinomas, 0/6 typical (well differentiated) carcinoids, 23/64 squamous cell carcinomas, 4/65 adenocarcinomas, and all 3 small cell lung cancer cell lines. All 8 neuroendocrine carcinomas, 11 of the Bcl-2-positive squamous cell carcinomas, and all 4 Bcl-2 positive adenocarcinomas expressed multiple neuroendocrine markers. The distributions of Bcl-2 and neuroendocrine marker immunoreactivity closely paralleled each other on consecutive sections. In squamous cell carcinomas, Bcl-2-positive cells could be roughly subdivided into those with neuroendocrine differentiation features, usually demonstrating intense Bcl-2 staining, with basaloid tumor cells usually expressing weak to moderate Bcl-2 staining. The present study clearly shows Bcl-2 protein expression to be remarkably differentially regulated according to histological types of lung cancers and to appear to quite likely be closely associated with neuroendocrine differentiation of tumor cells, indicating that bcl-2 is importantly involved in cell development and differentiation, in addition to protecting cells from apoptosis. Bcl-2 might be usable as a neuroendocrine marker in lung cancers and possibly also in neural-crest-derived tumors.     

Immunophenotypic predictive profiling of <Emphasis Type="Italic">BRCA1</Emphasis>-associated breast cancer

The immunophenotypic predictive profile of BRCA1-associated cancers including major predictive markers, i.e., PARP-1, EGFR, c-kit, HER-2, and steroid hormones (ER/PR) that may have therapeutic relevance has not yet been reported in a comprehensive study. Using immunohistochemistry, we examined the expression of these proteins in a large cohort of BRCA1-associated breast cancers. PARP-1 immunoreactivity was found in 81.9%, EGFR in 43.6%, ER/PR in 17.9%, c-kit in 14.7%, and overexpression of HER-2 in 3.6% of cancers. For all markers studied, 8.2% of tumors were negative. Expression of only one predictive marker was found in 29.7% of cancers, and most frequently, it was PARP-1 (20.8%). In 62.1% of tumors, more than one predictive marker was expressed: PARP-1 and EGFR in 30.4%, PARP-1, and hormone receptors in 13.3% and PARP-1 with c-kit in 7.5% of all tumors. Coexpression of two or more other predictive markers was rare. There were significant differences in the median age at diagnosis of BRCA1-associated cancer between patients with ER+ vs. ER− and grades 1–2 vs. grade 3 tumors. These results demonstrate that BRCA1-associated cancers differ with respect to expression of proteins that are regarded as targets for specific therapies and that 92% of patients with BRCA1-associated cancers may benefit from one or several options for specific therapy (in addition to DNA damaging agents, e.g., cisplatin). About 8% of cancers which do not express therapeutic target proteins may not respond to such therapies. Knowledge of the immunophenotypic predictive profile may help with the recruitment of patients for trials of targeted therapies.     

Frameshift mutations of autophagy‐related genes ATG2B,ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability

Mounting evidence indicates that alterations of autophagy processes are directly involved in the development of many human diseases, including cancers. Autophagy‐related gene (ATG) products are main players in the autophagy process. In humans there are 16 known ATG genes, of which four (ATG2B, ATG5, ATG9B and ATG12) have mononucleotide repeats with seven or more nucleotides. Frameshift mutations of genes with mononucleotide repeats are features of cancers with microsatellite instability (MSI). It is not known whether ATG genes with mononucleotide repeats are altered by frameshift mutations in gastric and colorectal carcinomas with MSI. For this, we analysed the mononecleotide repeats in ATG2B, ATG5, ATG9B and ATG12 in 32 gastric carcinomas with high MSI (MSI‐H), 13 gastric carcinomas with low MSI (MSI‐L), 43 colorectal carcinomas with MSI‐H and 15 colorectal carcinomas with MSI‐L by a single‐strand conformation polymorphism (SSCP) analysis. We found ATG2B, ATG5, ATG9B and ATG12 mutations in 10, 2, 13 and 0 cancers, respectively. The mutations were detected in MSI‐H cancers but not in MSI‐L cancers. Gastric and colorectal cancers with MSI‐H harboured one or more ATG mutations in 28.1% and 27.9%, respectively. Our data indicate that frameshift mutations in ATG genes with mononucleotide repeats are common in gastric and colorectal carcinomas with MSI‐H, and suggest that these mutations may contribute to cancer development by deregulating the autophagy process. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis

PurposeThis study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk.MethodsWe calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50–69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis.ResultsPolygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles.ConclusionTargeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer.     

Clear cell and endometrioid carcinomas: are their differences attributable to distinct cells of origin?

Endometrial epithelium is the presumed tissue of origin for both eutopic and endometriosis‐derived clear cell and endometrioid carcinomas. We had previously hypothesized that the morphological, biological and clinical differences between these carcinomas are due to histotype‐specific mutations. Although some mutations and genomic landscape features are more likely to be found in one of these histotypes, we were not able to identify a single class of mutations that was exclusively present in one histotype and not the other. This lack of genomic differences led us to an alternative hypothesis that these cancers could arise from distinct cells of origin within endometrial tissue, and that it is the cellular context that accounts for their differences. In a proteomic screen, we identified cystathionine γ‐lyase (CTH) as a marker for clear cell carcinoma, as it is expressed at high levels in clear cell carcinomas of the ovary and endometrium. In the current study, we analysed normal Müllerian tissues, and found that CTH is expressed in ciliated cells of endometrium (both eutopic endometrium and endometriosis) and fallopian tubes. We then demonstrated that other ciliated cell markers are expressed in clear cell carcinomas, whereas endometrial secretory cell markers are expressed in endometrioid carcinomas. The same differential staining of secretory and ciliated cells was demonstrable in a three‐dimensional organoid culture system, in which stem cells were stimulated to differentiate into an admixture of secretory and ciliated cells. These data suggest that endometrioid carcinomas are derived from cells of the secretory cell lineage, whereas clear cell carcinomas are derived from, or have similarities to, cells of the ciliated cell lineage. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.