The relationship of TMPRSS2-ERG gene fusion between primary and metastatic prostate cancers

Recent studies have revealed the presence of TMPRSS2-ERG gene fusion in both primary and metastatic prostate cancers. However, the relationship between primary and corresponding metastatic prostate cancers with respect to the status of this gene fusion remains unclear. Using fluorescence in situ hybridization, we evaluated the rearrangement of the ERG gene in the radical prostatectomy specimens and corresponding lymph node metastases from 19 patients with prostate cancer. The mean age of the patients was 61 years, and the median Gleason score in the radical prostatectomy specimens was 7 (4 + 3). Prostate cancer was unifocal in 6 cases and multifocal in 13 cases, including 10 with 2 foci and 3 with 3 foci. In the primary prostate cancers, rearrangement of the ERG gene was observed in 13 cases and associated with deletion of the 5' ERG gene in 8 cases. In the metastases, the ERG rearrangement was present in 10 cases and associated with deletion of the 5' ERG gene in 6 cases. In unifocal prostate cancers, the status of the ERG rearrangement was concordant between the primary prostate cancer and metastasis in 5 of 6 cases. In multifocal prostate cancer, despite a significant interfocal discordance, the status of the ERG rearrangement was concordant between the index (largest) primary tumor focus and metastasis in all 13 cases. Our study demonstrates a close relationship of the TMPRSS2-ERG gene fusion status between primary and metastatic prostate cancer. The concordance of the ERG gene rearrangement status between the index primary tumor focus and metastasis suggests that metastasis most likely arises from the index tumor focus in multifocal prostate cancer.     

Variation of alpha-methylacyl-CoA racemase expression in prostate adenocarcinoma cases receiving hormonal therapy

alpha-methylacyl-CoA racemase (AMACR) is widely used as a diagnostic marker of prostate adenocarcinoma. It is also used to identify residual adenocarcinoma cells in posthormonal therapy cases. However, there have been very few studies on the relationship between hormonal therapy, which is also called androgen withdrawal therapy and AMACR expression. Here, we carried out a study on AMACR expression in paired pre- and posthormonal therapy prostate adenocarcinoma cases using an immunohistochemical method and a digital imaging system to elucidate the relationship between AMACR expression and hormonal therapy. This study showed that AMACR expression was decreased in 65 of 98 paired cases after hormonal therapy (Mann-Whitney U test, P < .05). Wilcoxon analysis also demonstrated a difference in the AMACR digital average expression in all 98 cases (P < .0001). However, this variation in AMACR expression did not seem to have any relevance to the response to hormonal therapy (P = .5386). We propose that AMACR, as a diagnostic marker, should be carefully used in posthormonal therapy cases. Further investigation of the relationship between AMACR expression and androgen or androgen receptors may provide new insight into novel preventive and curative medicine for prostate adenocarcinoma.     

The relation of beclin 1 and bcl-2 expressions in high grade prostatic intraepithelial neoplasia and prostate adenocarcinoma: A tissue microarray study

The aim of the present study was to evaluate the expressions of beclin 1 and bcl-2 in prostate cancer (PC) and high grade prostatic intraepithelial neoplasia (HGPIN), and to investigate their relationship with clinicopathological parameters. The study included 30 benign prostatic hyperplasia (BPH), 40 HGPIN and 106 primary PC cases. The expressions of beclin 1 and bcl-2 were assessed semiquantitatively based on both the percentage and intensity of positive staining cells. Beclin 1 was positive in 27 (90%) BPH, 37 (92.5%) HGPIN, and 90 (84.9%) PC cases (p > 0.05). Bcl-2 immunostaining was detected in 99 (93.4%) PC, 37 (92.5%) HGPIN, and 9 (30%) BPH cases (p < 0.0001). Regarding expression scores, beclin 1 was significantly lower in PC cases than in the HGPIN and BPH groups (p < 0.0001), and it was also negatively correlated with Gleason score (p = 0.004, r = −0.274). Bcl-2 expression score was significantly higher in PC than in the other groups (p < 0.0001), and also positively correlated with Gleason score (p < 0.0001, r = 0.425). Furthermore, a negative correlation was found between bcl-2 and beclin 1 expression scores in PC cases (p = 0.006, r = −0.265). Our results suggest an association between bcl-2 and beclin 1 expressions in malignant transformation of prostate tissue and also in regulating PC cell differentiation, progression and the aggressiveness of PC.     

Haematobium eggs detection in human bladder cancer and sporocysts in snail vectors: Seven cases report and a review of the Burkina Faso literature

Schistosoma haematobium plays a central role in the development of bladder cancer in Burkina Faso. The objective of this study was to determine the presence of S. haematobium in the bladder cancer and in vector snails. For the first time, formalin-fixed tissues embedded in paraffin were analyzed by immunohistochemistry and PCR. Molecular detection has resulted in 7/7 positive bladder cancer. Finally, as the snail vectors were positive. We suggest the use of molecular methods in the snail vectors for the detection of cysts and in cancerous tissues in larger studies.     

Assessment of the HER2 status in breast cancer by fluorescence in situ hybridization: a technical review with interpretive guidelines

Diagnostic assays for HER2 in breast cancer provide important prognostic information and independently help guide management by identifying patients who are the most likely to benefit from Herceptin-targeted therapy. The biological events underlying HER2 -driven breast cancer that can be assessed in routine clinical specimens include the evaluation of gene amplification by fluorescence in situ hybridization (FISH), enhanced messenger RNA expression by real-time polymerase chain reaction, and the assessment of protein overexpression at the tumor cell membrane by immunohistochemistry (IHC). Immunohistochemistry and FISH methodologies have the advantage of being morphologically driven, allowing for correlations between HER2 expression and morphologic features. However, each has important advantages and disadvantages, which are discussed in detail. Although immunohistochemistry is familiar and readily accommodated in most surgical pathology laboratories, increasing demands for FISH testing in the clinical setting will require greater familiarity with the technical aspects of FISH assays and their interpretation by the greater laboratory community. In this review, we provide an overview of FISH testing for HER2 in breast cancer, with an emphasis on technical considerations, interpretive guidelines, scoring criteria, and quality control. The development of automated platforms for hybridization, image analysis for signal enumeration, and experience with FISH interpretation should broaden the availability of this technology for clinical diagnostic testing.     

Double-hit and triple-hit lymphomas arising from follicular lymphoma following acquisition of MYC: report of two cases and literature review

Double-hit or triple-hit B-cell lymphomas (DHL and THL) are rare subtype lymphomas usually associated with poor prognosis. It is defined by two or three recurrent chromosome translocations; MYC/8q24 loci, usually in combination with the t (14; 18) (q32; q21) bcl-2 gene or/and BCL6/3q27 chromosomal translocation. DHL was often observed both in de-novo diffuse large B cell lymphomas (DLBCL). It is otherwise unclassifiable, showing features intermediate that of large B-cell lymphoma and Burkitt lymphoma. Here, we present two follicular lymphoma patients; one transformed to THL, another transformed to DHL. Both cases revealed aggressive clinical courses with poor prognosis and associated with acquisition of c-Myc gene (MYC) and central nervous system (CNS) involvement. We reviewed the related literature, correlated the immunophenotype and clinical manifestations such as response to therapy and prognosis. Although the incidence of DHT and THL is low, cytogenetic and FISH analyses should be included when B-cell lymphoma patients experience relapse or refractory course of disease. We concluded that c-Myc may contribute to aggressive transformation, and more mechanism-based therapy should be explored.     

Transition between morule-like and solid components may occur in solid-predominant adenocarcinoma of the lung: report of 2 cases with EGFR and KRAS mutations

A limited number of pulmonary adenocarcinoma cases with morule-like components have been described to date, and the most frequent histological subtype is papillary-predominant adenocarcinoma. Occasionally, this type of adenocarcinoma is associated with solid-predominant adenocarcinoma. EGFR mutations are predominant in adenocarcinoma with morule-like components, followed by ALK rearrangements. Herein, we present 2 cases of solid-predominant adenocarcinoma with morule-like components harboring either an EGFR or KRAS mutation. This KRAS-mutant case is the first to be associated with morule-like components, to the best of our knowledge. Both cases showed transition between micropapillary and morule-like components. Transition between morule-like and solid components was also observed in both cases. Although a few cases of solid-predominant adenocarcinoma have been shown to harbor morule-like components, this type of transition has not been previously well described. We surmised that the solid components of some EGFR-mutant adenocarcinomas might be derived from morule-like components.     

Epithelioid inflammatory myofibroblastic sarcoma treated with ALK inhibitor: a case report and review of literature

Epithelioid inflammatory myofibroblastic sarcoma is extremely rare and belongs to a variant of inflammatory myofibrobalstic tumor with aggressive clinical course. We describe a case of a 22 years old man presented with an abdominal huge tumor. Microscopically, the neoplasm cells were rounded and epithelioid in shape. Abundant interstitial edema and less myxoid stroma were also present together with an inflammatory infiltrate. Fluorescence in situ hybridization revealed that ALK gene presented mutation. After surgery the patient received chemotherapy with an anaplastic lymphoma kinase (ALK) inhibitor, crizotinib. The patient continues to be alive with disease for 16 months and has no recurrence. Although EIMS has a poor prognosis, this is the few successful case with sustained response of targeted therapy.     

乳腺型外阴腺癌中HER-2扩增并文献复习

目的探讨乳腺型外阴腺癌的临床病理学特征、诊断及鉴别诊断。方法采用免疫组化En Vision两步法及荧光原位杂交法检测1例HER-2扩增的乳腺型外阴腺癌,并进行相关文献复习。结果患者95岁,右侧大阴唇菜花样赘生物,形态学类似乳腺浸润性导管癌。免疫表型:GATA-3、GCDFP-15、CK、CK7、E-cadherin均(+),HER-2(3+),ER、PR、CK20、p63、AR均(-);荧光原位杂交检测显示HER-2/neu基因扩增。乳腺型外阴腺癌发病年龄较高,发病率低,临床医师对存在异位的乳腺肿块及HER-2扩增检测未引起足够重视。结论乳腺型外阴腺癌临床极其罕见,其诊断依赖病理形态和免疫表型,检测HER-2扩增对其靶向治疗具有诊断价值。     

The incidence of topoisomerase II-alpha genomic alterations in adenocarcinoma of the breast and their relationship to human epidermal growth factor receptor-2 gene amplification: a fluorescence in situ hybridization study

Clinical and in vitro evidence supports the concept that human epidermal growth factor receptor-2 ( HER2 ) gene amplification prediction of response to anthracycline-based chemotherapy in breast cancer is not a direct effect of HER2 overexpression, but the result of coamplification of topoisomerase II-alpha ( TOP2A ). We investigated the relationship of TOP2A to HER2 genomic alterations by fluorescence in situ hybridization (FISH) and the correlations with polysomic states for chromosome 17 (CEP17). One hundred thirty-eight cases of breast cancer HER2 gene amplified by 2-color FISH ( HER2 /CEP17) were reevaluated with a 3-color probe set ( HER2 /CEP17/ TOP2A ) to investigate the frequency of coamplification and deletion of TOP2A . TOP2A was never amplified in the absence of HER2 amplification and was coamplified with HER2 in 68 (50%) of 137 cases; HER2 gene copy number was higher than the TOP2A copy number ( P < .01). Of the 137 cases with HER2 amplification, 23 (16%) showed a monoallelic deletion of TOP2A . Of the 43 cases not amplified for HER2 , 27 (63%) were CEP17 eusomic, 13 (30%) polysomic, and 3 (7%) monosomic. Of the HER2 nonamplified cases, 2 (5%) showed monoallelic deletion of both the HER2 and TOP2A . The current study demonstrates the complex interrelationship between the HER2 and TOP2A genes in breast cancer. The clinical implications of TOP2A amplification and deletion in breast cancer need to be further defined. If TOP2A gene dosage can be confirmed to correlate with tumor responsiveness to anthracycline-based therapy in the clinical setting, FISH testing for TOP2A status may be warranted to aid in the selection of the most appropriate therapy.     

Xp11.2易位/TFE3基因融合相关性肾癌的病理特征与临床分析

目的探讨Xp11．2易位／TFE3基因融合相关性肾癌的临床病理特征、免疫表型、鉴别诊断及预后。方法对11例Xp11．2易位／TFE3基因融合相关性肾癌进行光镜观察和免疫组织化学研究及随访10～112个月,并复习相关文献。结果11例肿瘤中女性7例,男性4例。年龄8～26岁,平均16、3岁。肿块直径2．5～6．0cm。光镜下癌组织呈两种结构,一种为腺管状、乳头状、巢状分布。细胞界限清楚,有大量透明或嗜酸性胞质。泡状染色质、核仁明显,沙砾体多见。另一种结构更加紧密,多见实性巢状结构,癌细胞缺乏大量的胞质,核仁不明显,沙砾体少见。免疫表型：本组11例均TFE3、CD10、a-甲酰基-CoA消旋酶（P504s）弥漫表达,细胞广谱角蛋白（CK—pan）、上皮细胞膜抗原（EMA）、波形蛋白仅部分病例表达,所有病例CK7、肾脏特异性钙黏蛋白（Ksp—cadherin）、CD117阴性表达。结论Xp11．2易位／TFE3基因融合相关性肾癌是一种少见肿瘤,诊断主要依据患者的年龄。病理学形态和免疫组织化学TFE3阳性。     

Metastatic prostatic adenocarcinoma to the brain and spinal cord: a contemporary clinicopathologic analysis of 30 cases

Metastatic prostatic adenocarcinoma (PCa) to lymph nodes and bone is well documented in the literature, however only case reports and small series of metastatic PCa to the brain and spinal cord with clinicopathologic analysis have been published. We identified 30 cases of metastatic PCa to the brain and spinal cord. The mean patient age was 67 years (range: 50 to 87 years). Thirteen (43%) cases involved the brain and 17 (57%) cases involved the spinal cord. Most of the cases (60%) were a single mass. Of the 13 cases involving the brain, the temporal lobe 6 (46%) was the most common site and the spinal cord lesions involved the thoracic region in 13/17 (76%) cases. All patients had one or more metastases to other organs. In 8 patients, the brain or spinal cord metastasis was the initial diagnosis of PCa. In the patients that had prior prostate biopsy specimens available, the Gleason score ranged from 3+3=6 (Grade group 1: indicating unsampled higher grade PCa) to Gleason score 4+5=9 (Grade group 5). Follow-up was available in 21 cases with a mean duration of 20 months (range: 1 to 130 months). This is one of the largest clinicopathologic studies to date of metastatic PCa to the brain and spinal cord. Although rare, metastatic PCa should be considered in the differential diagnosis of a solitary brain or spinal cord mass in male patients, even over a decade after the initial diagnosis of PCa.