Prediction of coexistent carcinomas risks by subjective EIN diagnosis and comparison with WHO classification in endometrial hyperplasias

Endometrial intraepithelial neoplasia (EIN) classification is proposed as a new diagnostic system to resolve the limitations of the World Health Organization (WHO) classification in routine practice. Our aim was to find out whether EIN classification excels the WHO classification regarding the accurate prediction of coexisting endometrial carcinomas (EC) in biopsy specimens.     

子宫内膜透明细胞癌分子分型临床应用及其与PD-L1表达的关系

目的 探讨子宫内膜透明细胞癌(endometrial clear cell carcinoma,ECCC)分子分型的临床应用及其与PD-L1表达的关系.方法 应用测序法检测15例ECCC根治手术标本中POLE突变情况,有突变者为POLE突变型;应用免疫组化法检测错配修复(mismatch repair,MMR)MLH1...     

Hormonal imbalance in two types of endometrial cancer and genetic polymorphism of steroidogenic enzymes

OBJECTIVES: Modern data on endometrial cancer (EC) incidence demonstrate that it is one of the most prevalent gynecologic malignancies. It is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism differently contribute into susceptibility to described types of this disease, namely to type I (which is considered to be hormone dependent) and type II. METHODS: Distribution of allelic polymorphisms of CYP17 (17alpha-hydroxylase/17,20-lyase), CYP19 (aromatase), catechol-O-methyltransferase (COMT) and CYP1B1 (primarily, estrogen 4-hydroxylase) genes was compared totally in 156 endometrial cancer patients, approximately two-third of who belonged (on the basis of case history and some characteristics of host and tumor) to type I of the disease, and one-third to type II. Blood leukocytes were used as source of normal DNA for PCR-genotyping. RESULTS: No differences were found in distribution of CYP17 and CYP1B1 genotypes between patients belonging to type I or II of the disease. On the other side, in case of CYP19, the ratio of incidence of A6A6 genotype to the frequency of A1A6 and A3A6 genotypes was higher in type II patients (1.0) than in type I patients (0.3). Besides, incidence of high activity (HH) COMT genotype was higher among patients with type I of disease than in patients with type II of it (33.3% versus 14.7%, OR=2.9, z=1.96, p=0.05) revealing tendency to the lower inactivation of catecholestrogens in the latter group. CONCLUSION: It may be suggested that more aggressive clinically and frequently receptor-negative type II of endometrial cancer is associated with indirect signs of mainly intratumoral hyperproduction of estrogens (excess of CYP19 A6A6 genotype) without their sufficient inactivation into methoxyderivatives that warrants further study.     

Distinction of low-grade endometrioid carcinoma in endometrial samplings from high-grade mimics: a practical pattern-based approach

Low grade endometrioid carcinoma may exhibit a diverse spectrum of morphological variations that mimic high grade cancers. In an endometrial sampling, the distinction between low grade endometrioid carcinoma versus higher grades or other tumor types of carcinoma directly affects clinical decisions regarding the type and extent of surgery and lymph node dissection. This review takes a practical pattern-based approach to this differential diagnosis, highlighting glandular, papillary, solid, spindle-cell, clear-cell rich, mucin-rich, and necrotic patterns of low grade endometrioid carcinoma. Morphological distinctions and immunohistochemical strategies for navigating common diagnostic pitfalls are discussed in alignment with the consensus recommendations on tumor typing from the 2019 International Society of Gynecological Pathologists' Endometrial Cancer Project.     

Lobular carcinoma metastasis to endometrial polyp unrelated to tamoxifen. Report of a case and review of the literature

Endometrial polyps are rare sites for metastatic breast carcinoma. Such cases have mostly been reported in tamoxifen-related polyps. We report a case of lobular carcinoma with metastasis to an endometrial polyp in a patient with no history of tamoxifen therapy. The histological features of the polyp in our case closely mimicked those of tamoxifen-related polyps, emphasizing the fact that although characteristic-these features are not specific for tamoxifen. This case also reiterates the need for careful evaluation of endometrial polyps, since inconspicuous deposits of lobular carcinoma can easily be missed.     

白细胞相关免疫球蛋白样受体-1在宫颈癌和子宫内膜癌患者外周血T细胞的表达及意义

目的 研究白细胞相关免疫球蛋白样受体(LAIR-1)在宫颈癌和子宫内膜癌患者外周血T细胞的表达情况,并与子宫肌瘤、子宫癌前病变患者相比较,探讨LAIR-1表达与肿瘤免疫的相关性.方法 密度梯度离心法分离外周血单个核细胞,流式细胞术检测LAIR-1在196例肿瘤患者外周血T细胞的表达水平.结果 流式细胞术检测结果显示,宫颈癌和子宫内膜癌患者外周血CD3+CD4+T细胞LAIR-1阳性率均高于子宫肌瘤(P＜0.001;P＜0.05)和癌前病变患者(P ＜0.001;P ＜0.01).平均荧光强度分析结果显示,宫颈癌患者外周血CD3+CD4+T细胞LAIR-1表达水平显著高于癌前病变患者(P＜0.01),CD3+CD8+T细胞LAIR-1表达水平显著高于子宫肌瘤患者(P＜0.05)和癌前病变患者(P＜0.001).子宫内膜癌患者外周血CD3+CD4+T细胞LAIR-1表达水平明显高于子宫肌瘤患者(P＜0.05)和癌前病变患者(P＜0.01),CD3+CD8+T细胞LAIR-1表达水平高于癌前病变患者(P＜0.05).结论 LAIR-1在宫颈癌和子宫内膜癌患者外周血T细胞表达上调,提示LAIR-1可能与肿瘤免疫逃逸存在相关性.     

Molecular profiling pleomorphic lobular carcinomas of the breast: evidence for a common molecular genetic pathway with classic lobular carcinomas

Pleomorphic lobular carcinomas (PLC) of the breast display histological features associated with classic invasive lobular carcinoma (ILC), yet they also exhibit more conspicuous nuclear atypia and pleomorphism, and an aggressive clinical behaviour. From a breast cancer progression perspective, it is unclear whether PLC is a variant of ILC or is a high-grade invasive ductal carcinoma (IDC) that has lost E-cadherin. The molecular features of 26 PLC were studied using immunohistochemistry [oestrogen receptor (ER), progesterone receptor (PR), HER2, p53 and E-cadherin], 0.9 Mb resolution, microarray-based comparative genomic hybridization (aCGH), fluorescent (FISH) and chromogenic (CISH) in situ hybridization and loss of heterozygosity. Comparative analysis was performed with aCGH data from PLC with classic ILC (16 cases) and high grade IDC (35 cases). PLCs were frequently ER- and PR-positive, E-cadherin-negative and occasionally HER2- and p53-positive. Recurrent copy number changes identified by aCGH included gains on 1q, 8q, 11q, 12q, 16p and 17q and losses on 8p, 11q, 13q, 16q and Xq. Highly recurrent 1q+ (100% of cases), 16p+ (93%), 11q- (53%) and 16q- (93%) and evidence of the der(1;16)/der(16)t(1;16) rearrangement, as detected by FISH, suggested that PLC had a 'lobular genotype'. Focal amplifications were evident at 8p12-p11, 8q24, 11q13.1-q14.1, 12q14, 17q12 and 20q13. Loss of BRCA2 was detected in 40% of PLC by LOH. Comparative analysis of aCGH data suggested the molecular features of PLC (ER/PR-positive, E-cadherin-negative, 1q+, 11q(-), 16p+ and 16q(-)) were more closely related to those of ILC than IDC, implicating an overlapping developmental pathway for these lobular tumour types. Molecular alterations found in PLC that are more typical of high-grade IDC than ILC (p53 and HER2 positivity, 8q+, 17q24-q25+, 13q(-) and amplification of 8q24, 12q14, 17q12 and 20q13) are likely to drive the high-grade and more aggressive biology of PLC.     

Molecular subtypes of breast carcinoma in Egyptian women: clinicopathological features

Breast carcinoma may be classified into distinct molecular subtypes based on immunohistochemical markers for estrogen, progesterone and Her-2/neu receptors. The aim of the study was to identify the clinicopathological features of the molecular subtypes of breast carcinoma in our locality. A total of 274 surgically resected breast carcinomas were selected from the files of the Dr. KRZ referral pathology laboratory, Mansoura, Egypt, and the Pathology Department of Mansoura University. Molecular subtypes were classified into luminal A, luminal B, Her-2/neu-expressing and triple-negative. Clinicopathological and histological features of molecular subtypes were analyzed. Luminal A subtype was the most prevalent (41.2%), followed by triple-negative subtype (28.5%), then Her2-expressing subtype (19.4%) and luminal B subtype (13.9%). The commonest histological type was infiltrating duct carcinoma (83.2%), followed by infiltrating lobular carcinoma (9.1%) and medullary carcinoma (3.2%). The luminal A subtype was significantly correlated to low tumor grade, lower number of positive lymph nodes metastasis, absence of both necrosis and syncytial growth pattern. We concluded that the commonest molecular subtype of invasive breast carcinoma among Egyptian women is luminal subtype A, which displayed favorable features. Triple-negative subtype and medullary carcinomas are present in a ratio higher than in western countries.     

Comparative genomic hybridization reveals genetic progression of oral squamous cell carcinoma from dysplasia via two different tumourigenic pathways

To clarify the genetic pathway(s) involved in the development and progression of oral squamous cell carcinoma (OSCC), as well as the relationship between genetic aberrations and biological characteristics of OSCC tumours, comparative genomic hybridization was used to analyse genetic alterations in both primary OSCCs and adjacent dysplastic lesions of the same biopsy specimens from 35 patients. Gain of 8q22-23 was the most frequent alteration in both OSCC and mild dysplasia, and was considered the earliest event in the process of oral tumourigenesis. The average number of DNA sequence copy number aberrations (DSCNAs) increased with progression from mild dysplasia to invasive carcinoma (r = 0.737, n = 70, p < 0.001). OSCC samples were classified as having a large or small number of DSCNAs (OSCC-L, 21.4 +/- 4.7 DSCNAs or OSCC-S, 10.0 +/- 1.7 DSCNAs, respectively; p < 0.0001). Gains of 3q26-qter, 8q, 11q13, 14q, and 20q and losses of 4q, 5q12-22, 6q, 8p, 13q, and 18q22-qter were common to OSCC-L and OSCC-S. Gains of 5p15, 7p, 17q11-22, and 18p and losses of 3p14-21, 4p, and 9p were detected exclusively in OSCC-L. The average number of DSCNAs depended on whether the samples showed OSCC- L or dysplasia plus OSCC-L, or showed OSCC-S or dysplasia plus OSCC-S (p = 0.001). Gain of 5p15 and losses of 4p and 9p were detected even in dysplastic lesions adjacent to OSCC-L samples. Loss of 4p was associated with node metastasis by multivariate analysis (p = 0.013). OSCC-L tumours were more often T3-T4 stage tumours than T1-T2 stage tumours (p = 0.03). These findings suggest that two different types of OSCC, OSCC-L associated with high-stage cancer and OSCC-S associated with low-stage cancer, arise from different types of dysplasia via different genetic pathways.     

The association of mast cell density with myometrial invasion in endometrial carcinoma: A preliminary report

It is known that cancer is not a single transformational event. It is rather a multistage process involving complex interactions with the surrounding cellular microenvironment. Mast cells accumulate at sites of tumor growth in response to numerous chemoattractants. Our aim was to investigate the relationship between mast cell density (MCD) and myometrial invasion in endometrial carcinomas.     

PIK3CA gene mutations in endometrial carcinoma: correlation with PTEN and K-RAS alterations

Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway are common in endometrial carcinoma. Inactivation of the tumor suppressor gene PTEN leads to a constitutively active PI3K pathway, which plays a role in the early steps of endometrial tumorigenesis. Other alterations in the PI3K/AKT pathway are mutations in the PIK3CA gene, which encode the p110alpha catalytic subunit of PI3K. PIK3CA mutations cluster to the helical (exon 9) and the kinase (exon 20) domains of the gene. In endometrial carcinomas, PIK3CA mutations have been found to coexist frequently with PTEN mutations, but it is not clear whether they occur in cells with monoallelic or biallelic inactivation of PTEN. In the present study we have evaluated PIK3CA mutational status in a series of 33 endometrial carcinomas, previously screened for microsatellite instability and mutations in PTEN, K-RAS, and CTNNB-1. The tumors were also evaluated for loss of heterozygosity on 10q23 and hypermethylation of the promoter region of PTEN/psiPTEN to assess the monoallelic or biallelic inactivation status of PTEN. PIK3CA mutations were detected in 8 (24%) of the 33 cases. Seven mutations were located in exon 20 and 1 in exon 9. PTEN alterations were found in 19 cases (57%). Biallelic inactivation of PTEN was demonstrated in 11 tumors, whereas 8 tumors exhibited alteration in only 1 of the 2 alleles. PIK3CA mutations coexisted with monoallelic alterations of PTEN in 4 cases (2 mutations and 2 allelic imbalances), with biallelic PTEN inactivation in 1 case (mutation and promoter methylation), and 3 tumors showed PIK3CA mutations in association with wild-type PTEN. PIK3CA mutations did not correlate with microsatellite instability or mutations in CTNNB-1. However, PIK3CA and K-RAS mutations (8 cases) were mutually exclusive alterations. In summary, the results confirm that PIK3CA mutations are frequent in endometrial carcinoma and support the hypothesis that PIK3CA mutations may have an additive effect to PTEN monoallelic inactivation in endometrial carcinoma.     

Comparative genomic hybridization of ductal carcinoma in situ of the breast—evidence of multiple genetic pathways

There is strong evidence that ductal carcinoma in situ (DCIS) represents a precursor lesion of invasive breast cancer. In order to analyse specific chromosomal alterations of DCIS, 38 paraffin-embedded specimens of DCIS and six associated invasive carcinomas were examined by means of comparative genomic hybridization (CGH). Losses of 16q material were seen almost exclusively in well- and intermediately-differentiated DCIS. These two subgroups differed in the average number of genetic imbalances, 2·5 and 5·5 respectively. Additionally, a higher frequency of gains of 1q and losses of 11q material was seen in intermediately-differentiated in contrast to well-differentiated DCIS. Poorly-differentiated DCIS displayed a higher frequency of amplifications (17q12, 11q13) and a higher average rate of genetic imbalances (7·1). Analysis of adjacent invasive breast carcinoma revealed a genetic pattern almost identical to the one seen in the DCIS counterpart. These data characterize DCIS as a genetically far-advanced, heterogeneous lesion and as a direct precursor of invasive breast cancer. Copyright © 1999 John Wiley & Sons, Ltd.     

Molecular alterations differentiate microinvasive carcinoma from ductal carcinoma in situ and invasive breast carcinoma: retrospective analysis of a large single-center series

Microinvasive carcinoma (MIC) of the breast is a rare lesion. The clinicopathologic features and biologic behavior of MIC are unclear. Whether MIC is a distinct entity or an interim stage in the progression from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) remains to be determined. A retrospective review of clinicopathologic features and analysis of the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 in patients with MIC (90 cases), DCIS (268 cases) and IBC (1504 cases) was performed. Most MICs (93.3%) exhibited an intermediate to high nuclear grade, and this proportion was larger than that of DCIS (62.7%, P < 0.001) or IBC (85.4%, P = 0.036). The incidence of sentinel lymph node metastasis in MIC (12.5%) was higher than that of DCIS (1.6%, P < 0.001), but much lower than that of IBC (39.7%, P < 0.001). MICs had higher expression of HER-2 and lower expression of ER and PR compared to DCIS and IBC; and MIC was more likely to present with a HER-2+ subtype. Furthermore, DCIS exhibited greater HER-2 overexpression or gene amplification (P < 0.001) levels and lower proliferation index of Ki-67 (P < 0.001) compared to IBC. Our results suggest that the clinicopathologic and molecular phenotype of MIC are different from DCIS and IBC. Thus, MIC may be a distinct entity rather than an interim stage in the progression from DCIS to IBC. The prognosis of MIC and the biologic behavior of this uncommon subset need to be further explored.     

Clear cell papillary renal cell carcinoma: A chromosomal microarray analysis of two cases using a novel Molecular Inversion Probe (MIP) technology

Chromosomal microarray analysis using novel Molecular Inversion Probe (MIP) technology demonstrated 2,570 kb copy neutral LOH of 10q11.22 in two clear cell papillary renal cell carcinomas. In addition, one of the tumors had a big 29,784 kb deletion of 13q11-q14.2. There were two variants of unknown significance, a 2,509 kb gain of Xp22.33 and a 257 kb homozygous deletion of 8p11.22. The somatic mutation panel containing 74 mutations in nine genes did not reveal any mutations. Besides identification of submicroscopic duplications or deletions, SNP microarrays can reveal abnormal allelic imbalances including LOH and copy neutral LOH, which cannot be recognized by chromosome, FISH, and non-SNP microarray arrays. To the best of our knowledge, this is the first study demonstrating copy neutral LOH of 10q11.22 in clear cell papillary renal cell carcinomas using the new MIP SNP OncoScan FFPE Assay Kit on formalin-fixed paraffin-embedded tumor samples.     

Molecular genetic changes in epithelial, stromal and mixed neoplasms of the endometrium

Endometrial carcinoma, endometrial stromal tumours and mixed malignant mesodermal tumours (MMMT) develop along distinctive molecular genetic pathways. Two distinctive types of endometrial carcinoma are distinguished, type I and type II, which develop along distinctive pathways and show different clinical behaviour and histological features. Type I carcinomas show endometrioid histology, are oestrogen-related and develop from atypical endometrial hyperplasia. The molecular tumorigenesis is comparable to colorectal carcinoma with a step-like progression and an accumulation of genetic alterations. Alterations of PTEN, K-Ras mutations and microsatellite instability are frequent and early events in type I carcinoma, whereas p53 mutations occur during progression to grade 3 carcinoma. Serous and clear cell carcinomas are considered type II carcinomas which are mostly unrelated to oestrogen. p53 mutations occur in almost all serous carcinomas and seem to occur early, leading to massive chromosomal instability and rapid tumour progression. Gene expression profiling has supported this dualistic model of endometrial carcinoma. There is evidence of molecular differences between serous and clear cell carcinomas as well as between endometrioid carcinomas with and without microsatellite instability. A dualistic model of tumorigenesis may be also suggested for endometrial stromal tumours. Endometrial stromal sarcomas (ESS; type I endometrial sarcoma) are oestrogen-related and seem to develop from endometrial stromal nodules (ESN). They are histologically and genetically distinct from undifferentiated endometrial sarcoma (UES) which seem to be mostly unrelated to oestrogen (type II endometrial sarcoma). ESS and ESN share the fusion gene JAZF1/JJAZ1 caused by a t(7;17)(p15;q21) translocation, whereas UES lacks a distinctive molecular alteration so far. In MMMT, which is considered a metaplastic carcinoma, p53 alteration occurs early, before clonal expansion and acquisition of genetic diversity during progression.