Chromophobe renal cell carcinoma: clinical, pathological and molecular biological aspects

Chromophobe renal cell carcinoma (RCC), a newly established subtype of renal neoplasm, is composed of tumor cells with characteristically cloudy, weakly eosinophilic and reticular cytoplasm. The tumor should be distinguished from the common clear cell RCC, because of the unique clinicopathological and molecular biological features. The tumor does not show gender bias. Patient ages are similar to those of clear cell RCC, but might occur in the 20- to 40-year-old age group. Grossly, the tumor tends to be beige in color, which is different from the yellowish color of common RCC. Electron microscopy and immunohistochemistry indicate the intercalated cell of the collecting duct as the cellular origin. Cytogenetic study shows non-random multiple chromosome loss, with mitochondrial DNA rearrangement. Alteration of the von Hippel-Lindau (VHL) gene, a cancer suppressor gene relating with clear cell RCC, has not yet been observed. In order to adopt the most appropriate treatment, including gene therapy, recognition and correct pathological diagnosis of chromophobe RCC are extremely important.     

Pediatric renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion

Renal cell carcinoma (RCC) in children and young adults is rare and pathologically problematic. RCC can be either hereditary or sporadic and has a guarded prognosis because appropriate management has not been established. A case of RCC in an 11-year-old is reported. The clinical presentation was a right abdominal mass, hematuria, urinary tract infection, and wasting. Radio-logically, the mass was found within the right kidney with calcification and paraaortic lymphadenopathy. The postsurgical diagnosis was Wilms' tumor stage T4N2M0. On gross inspection, the tumor was ill defined, extending across Gerota's fascia and into the ureter lumina. Microscopically, the tumor consisted of malignant epithelial cells with clear and eosinophilic cytoplasm in nested, papillary, and alveolar configuration. Hyaline nodules, psammoma bodies, vascular invasion, capsular invasion, and extension into the ureter were also found. Immunohistochemically, the cells showed strong nuclear immunoreactivity for TFE3. We concluded that this case was an RCC associated with Xp11.2 translocation/TFE3 fusion, Fuhrman grade 3, stage IV.     

A case of renal transitional cell carcinoma associated with synchronous contralateral renal cell carcinoma

We report a case of simultaneous contralateral renal transitional cell carcinoma and renal cell carcinoma. A 63-yr-old male presented with hematuria. He was diagnosed with left renal pelvis tumor and contralateral renal cell carcinoma. Subsequently, the patient received left nephrectomy and paraaortic lymphadenectomy (transitional cell carcinoma, pT3N2M0). Post-operatively, chemotherapy of renal pelvis tumor and angioinfarction of contralateral renal cell carcinoma are being considered. We believe that management planning should be individualized in such cases.     

Protein expression profiles and prognostic value of E2F family members in clear cell renal cell carcinoma

The derangement of the cell cycle facilitates uncontrolled cell proliferation and acquisition of genetic alterations favorable for malignancy. However, the protein expression profiles of E2 F family cell cycle regulators in clear cell renal cell carcinoma (ccRCC) have not yet been thoroughly investigated. In this study, we aimed to examine the protein expression profiles and prognostic value of E2 F1, E2 F3, and E2 F4 in ccRCC cases. The immunohistochemical expression of E2 F1, E2 F3, and E2 F4 was quantitatively scored in 180 ccRCC tumor tissues and 79 normal kidney tissues. The prognostic implications of these E2 F members were determined. We found that ccRCC tumor cells showed higher nuclear expression of E2 F1, E2 F3 and E2 F4 than normal kidney samples. High E2 F1 and E2 F3 expression in tumor cells was associated with poor prognostic factors of ccRCC, whereas high E2 F4 correlated with beneficial prognostic factors. High expression of E2 F1 and E2 F3 in tumor cells was correlated with a poor overall and recurrence-free survival, while high E2 F4 expression did not. In conclusion, E2 F1, E2 F3 and E2 F4 may function as oncogenes during tumorigenesis of ccRCC, although they contribute to the progression of ccRCC in different ways. Additional studies are required to clarify the conflicting role of E2 F4 in the tumor evolution of ccRCC.     

Proliferative activity of renal cell carcinoma associated with acquired cystic disease of the kidney: comparison with typical renal cell carcinoma

To assess the proliferative activity of renal cell carcinoma (RCC-A) in patients with acquired cystic disease of the kidney (ACDK) after long-term hemodialysis, we analyzed cell cycle, DNA ploidy, and S-phase fraction by flow cytometry (FCM) and proliferating cell nuclear antigen (PCNA) labeling index by immunohistochemistry. The data were compared with those of typical RCC (tRCC). Sixteen (88.9%) of 18 RCC-As showed a diploid pattern. The values of cells at each phase in the cell cycle in RCC-A group (S, 4.36% + 2.16%; G2M, 5.06% + 1.90%; S+G2M, 9.41% + 2.81%; P <.05) were significantly different from those of tRCCs (S, 8.91% + 6.58%; G2M, 8.77% + 5.73%; S+G2M; 17.67% + 7.61%). The PCNA labeling index was statistically significantly lower in the RCC-As (24.01% +/- 13.4%; P <.05) than in tRCCs (42.27% +/- 26.1%). These results indicate that the RCC-As are less proliferative than tRCC and are consistent with the observation that RCC-As are less aggressive neoplasms.     

儿童肾细胞癌3例临床病理分析

目的：探讨儿童肾细胞癌(renal cell carcinoma,RCC)的临床病理特征、分类、诊断与鉴别诊断。方法：收集2003年~至今湖南省儿童医院3例儿童RCC病例,其中男性2例,女性1例,年龄5.5~9岁。进行光镜及免疫组化检测重新分类。结果：1例镜下以乳头状结构排列胞浆透亮的癌细胞为主,乳头间可见纤维、血管及炎细胞浸润,伴有较多钙化小体结构;其余2例镜下均以实性巢索状、腺管状排布的嗜酸性颗粒癌细胞为主,灶性区域有少量透明癌细胞排列成不典型乳头状结构,未见钙化小体;免疫组化结果：其中1例表达TFE3、Vimentin、CK-pan和CEA;第2例表达Vimentin、CK-pan、CEA及p53;第3例表达Vimentin、CK-pan、CEA、NSE、CgA、Syn及Ki-67。结论：儿童RCC较少见,HE形态下以乳头状结构排列的透明癌细胞类型需结合TFE3免疫组织化学或基因检测等手段明确诊断。术前采用静脉化疗能提高肿瘤完整切术率。儿童RCC整体预后与成人相比较好,但Xp11.2易位/TFE3基因融合相关性肾癌(Xp11 RCC)预后较透明细胞性肾细胞癌(clear cell renal cell carcinoma,CCRCC)差,由于其在儿童期多表现为惰性进展,需长期的随访观察。     

Tubulocystic carcinoma of kidney associated with papillary renal cell carcinoma

Tubulocystic renal cell carcinoma (TCRCC) is a rare variant of renal cell carcinoma, which has distinct histology but there is some controversy about its association with papillary renal cell carcinoma (PRCC) and cell of origin in literature. We report an 18-year-old girl with the rare TCRCC of kidney associated with PRCC with metastases to the para-aortic nodes. The patient presented with hematuria and a right renal mass with enlarged regional nodes for which a radical nephrectomy with retroperitoneal lymph node dissection was done. On gross examination, a solid cystic lesion involving the lower pole and middle pole of the kidney measuring 12x9x9 cm was seen along with an additional cystic lesion in upper pole of kidney. Microscopically the main tumor showed the typical histology of a tubulocystic carcinoma with multiple cysts filled with secretions lined by variably flattened epithelium with hobnailing of cells. The mass in the upper pole was a high-grade PRCC and the nodal metastases had morphology similar to this component. To conclude, at least a small but definite subset of TCRCC is associated with PRCC, and cases associated with PRCC do seem to have a higher propensity for nodal metastasis as in the case we report.     

三叶因子3对甲状腺乳头状癌细胞周期的影响及机制

目的 探讨三叶因子3 (TFF3)基因沉默对人甲状腺乳头状癌TPC-1和BCPAP细胞增殖及细胞周期的影响及相关分子机制。 方法 包装TFF3 shRNA 慢病毒载体,病毒感染获得TPC-1和BCPAP稳转细胞株;生长曲线和集落形成实验检测沉默TFF3后细胞增殖状况;流式细胞术检测TFF3基因对TPC-1和BCPAP细胞周期的影响;实时定量聚合酶链反应(Real-time PCR)检测P27、P21和cyclin D1、周期蛋白依赖性激酶（CDK）4 mRNA的表达情况;免疫印迹法(Western blotting)、免疫细胞化学染色检测周期相关蛋白P27、P21、cyclin D1、CDK4和蛋白激酶B（Akt）、pAkt的蛋白表达水平。 结果 成功包装TFF3 shRNA 慢病毒载体,病毒液感染获得TPC-1和BCPAP稳转细胞株;生长曲线和集落形成实验结果显示,沉默TFF3后,细胞增殖能力减弱;流式细胞术结果显示,与对照组相比,TFF3基因沉默组G₁期的细胞比例明显增高(*P<0.05),S和G2期的细胞比例明显下降（*P<0.05);TFF3沉默组TPC-1和BCPAP细胞中的P27、P21 mRNA和蛋白明显上调（*P<0.05),而cyclin D1,CDK4 mRNA和蛋白表达降低（*P<0.05);4株细胞Akt蛋白含量无明显差异,但沉默TFF3组磷酸化蛋白激酶B（pAkt）表达减弱;免疫细胞化学染色显示,cyclinD1阳性蛋白位于癌细胞胞核,P27、P21蛋白表达于胞质和胞核,且沉默TFF3后在细胞核中阳性信号增强,细胞质中阳性表达降低。 结论 沉默TFF3可明显延长甲状腺癌细胞周期,抑制细胞的增殖,可能与抑制磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/Akt）通路相关蛋白的表达有关。     

Proteus syndrome review: molecular,clinical, and pathologic features

Proteus syndrome is caused by an activating AKT1 mutation (c.49G>A, p.Glu17Lys). Many variable features are possible in this mosaic disorder, including: (i) disproportionate, asymmetric, and distorting overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform connective tissue nevus made up of highly collagenized connective tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis; (v) vascular malformations of the capillary, venous, or lymphatic types; (vi) dysregulated adipose tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits; (vii) other unusual features, including bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and (viii) deep vein thrombosis, resulting in premature death. Concluding remarks address diagnostic criteria, natural history, management, psychosocial issues, and differential diagnosis.     

Endometrioid carcinoma of the endometrium: pathologic and molecular features

Endometrioid carcinoma of the endometrium is the most common type of endometrial carcinoma. The microscopic appearance of the tumor resembles that of the proliferative endometrium, with a variable degree of glandular complexity and cellular pleomorphism. Several subtypes have been described, including the presence of squamous differentiation, villoglandular pattern, secretory features and ciliated cells. Recently recognized subtypes are the tumors that arise in the setting of hereditary nonpolyposis colon cancer syndrome, tumors with small nonvillous papillae, presence of microglandular pattern, sertoliform features, and dedifferentiated carcinomas. The main differential diagnosis includes endocervical adenocarcinoma, atypical polypoid adenomyoma, malignant mixed Müllerian tumors, and metastatic tumors to the endometrium. The main prognostic factors are stage, histologic grade, myometrial, cervical and vascular invasion. There are several pathologic features that should be recognized to avoid underestimation of these prognostic factors, such as presence of MELF pattern of myometrial invasion, and invasion of the cervical stroma with a deceptive pattern of spread. Six different molecular features are frequent in this type of tumor, including microsatellite instability, and mutations in PTEN, k-RAS, PIK3CA, FGFR2 and CTNNB1.     

琥珀酸脱氢酶缺陷型肾细胞癌的临床病理学、超微结构及分子特征

目的探讨琥珀酸脱氢酶缺陷型肾细胞癌(succinate dehydrogenase-deficient renal cell carcinoma, SDH RCC)的临床病理特征、免疫表型、超微结构、分子特征及鉴别诊断。方法对解放军东部战区总医院2010至2019年间11例SDH RCC进行光镜观察、免疫组织化学染色、超微结构研究及随访, 并对其中7例进行高通量DNA靶向测序, 分析其分子病理特征。结果 11例患者中女性4例, 男性7例。患者年龄24～62岁, 平均年龄41.4岁, 中位年龄41岁。低倍镜下, 该类型肾癌以实性片状、小管状结构为主, 局部有微囊改变, 其中4例呈巢团状、梁索状结构分布于疏松水肿的间质或瘢痕周围, 类似于嗜酸细胞腺瘤。高倍镜下, 肿瘤细胞胞质呈絮状嗜酸性, 可见特征性的半透明空泡。琥珀酸脱氢酶B在8例中呈明确阴性表达, 有阳性内对照;其余3例肿瘤细胞呈片状或灶性微弱表达, 而肿瘤内正常肾小管及血管内皮细胞呈强阳性表达。高通量DNA靶向测序显示, 7例送检病例(包括3例琥珀酸脱氢酶B表达不明确的病例)中均检测出琥珀酸脱氢酶B基因致病性突变, 未见琥珀酸脱氢酶...     

MR imaging of renal cell carcinoma: associations among signal intensity, tumor enhancement, and pathologic findings

The purpose of this study was to compare the MR characteristics of renal cell carcinomas against histologic findings and to assess the correlations among signal intensity, tumor enhancement, and pathologic findings. Fifty-four patients (56 lesions) were examined by MR imaging and then underwent partial or radical nephrectomy. The pathologic diagnosis of all lesions was renal cell carcinoma. All MR examinations were performed as dynamic studies using the same 1.5-T scanner. MR characteristics were compared against pathologic findings after resection, and the correlations among signal intensity, tumor enhancement, and pathologic findings were then assessed. A significant correlation was observed between tumor grade and tumor enhancement, with G3 lesions tending to show little enhancement. Regardless of the histologic classification, G3 tumors were found to contain highly heterotypic cancer cells and very few vessels by histopathologic examination. No significant correlations were noted between the other MR characteristics and pathologic findings. Renal cell carcinomas showing little enhancement tend to be highly malignant lesions based on the pathologic findings. Special consideration is required for these tumors with regard to the selection of surgical intervention and follow-up observation.     

The new bone biology: pathologic, molecular, and clinical correlates

Bone and cartilage and their disorders are addressed under the following headings: functions of bone; normal and abnormal bone remodeling; osteopetrosis and osteoporosis; epithelial-mesenchymal interaction, condensation and differentiation; osteoblasts, markers of bone formation, osteoclasts, components of bone, and pathology of bone; chondroblasts, markers of cartilage formation, secondary cartilage, components of cartilage, and pathology of cartilage; intramembranous and endochondral bone formation; RUNX genes and cleidocranial dysplasia (CCD); osterix; histone deacetylase 4 and Runx2; Ligand to receptor activator of NFkappaB (RANKL), RANK, osteoprotegerin, and osteoimmunology; WNT signaling, LRP5 mutations, and beta-catenin; the role of leptin in bone remodeling; collagens, collagenopathies, and osteogenesis imperfecta; FGFs/FGFRs, FGFR3 skeletal dysplasias, craniosynostosis, and other disorders; short limb chondrodysplasias; molecular control of the growth plate in endochondral bone formation and genetic disorders of IHH and PTHR1; ANKH, craniometaphyseal dysplasia, and chondrocalcinosis; transforming growth factor beta, Camurati-Engelmann disease (CED), and Marfan syndrome, types I and II; an ACVR1 mutation and fibrodysplasia ossificans progressiva; MSX1 and MSX2: biology, mutations, and associated disorders; G protein, activation of adenylyl cyclase, GNAS1 mutations, McCune-Albright syndrome, fibrous dysplasia, and Albright hereditary osteodystrophy; FLNA and associated disorders; and morphological development of teeth and their genetic mutations.     

Chromosomal abnormalities of clear cell renal cell carcinoma: Frequent gain of chromosome 7

Gain of chromosome 7 is well known to be a characteristic abnormality of papillary renal cell carcinoma (RCC). The purpose of the present study was to perform cytogenetic analysis of G-band karyotype in 16 clear cell RCC obtained from nephrectomy. The age of patients ranged from 50 to 79 years and the tumor size in largest dimension ranged from 1.8 to 6.2 cm. As a result, the structural abnormality of chromosome 3 was most frequently observed (eight clones). Loss of chromosome 3 and gain of chromosome 7 followed (four clones). Among four clones showing gain of chromosome 7, two were associated with the abnormality of chromosome 3 and the remaining two were devoid of the abnormalities of chromosome 3. In addition, none of all four tumors showing gain of chromosome 7 demonstrated any foci of papillary growth pattern. The present study shows that gain of chromosome 7 is not exclusive to papillary RCC, but it can be found in clear cell RCC as well, and this finding may represent a diagnostic pitfall in distinguishing clear cell RCC from papillary RCC.     

肾脏黏液性管状和梭形细胞癌的临床及病理学特点

目的 探讨肾脏黏液性管状和梭形细胞癌的临床病理学特点.方法 分析7例肾脏黏液性管状和梭形细胞癌的临床特点、组织形态及免疫表型特点[CD10、CK7、CK18、CK19、Villin、上皮细胞膜抗原(EMA)、P504S和波形蛋白],并复习相关文献.结果 7例黏液性管状和梭形细胞癌中,男性3例,女性4例,平均年龄48.2岁(39～61岁).均为体检时发现肿瘤,肿瘤最大径平均5.5 cm(4.0～9.0 cm),术后随访18～51个月,得到随访资料的5例均无复发及转移.肿瘤大体切面均为实性、灰白色,无包膜,但与周围肾组织分界清晰.镜下观察肿瘤细胞主要由两种形态构成:均一的由立方细胞构成的紧密排列的小管状结构和梭形细胞成分.两种成分比例或多或少,交错分布,其中5例伴有黏液样基质,3例见到明显的透明细胞区域,1例可见灶状肉瘤样区域,1例见乳头状结构及泡沫细胞.免疫组织化学染色显示,7例肿瘤CK7均呈阳性表达,EMA、CK18和P504S在染色的5例中全部呈阳性表达,CK19在染色的5例中有4例表达,而CD10、Villin和波形蛋白表达差异较大.结论 肾脏黏液性管状和梭形细胞癌是一种低度恶性的多形性肿瘤,组织形态学谱系较宽,不典型的病例可以主要由两种成分之一构成,并缺少黏液,有些病例可见到透明细胞、乳头状结构,少数可见肉瘤样形态及坏死.免疫表型上对于从近曲小管到集合管的标志物均有表达.

Abstract：

Objective To investigate the clinical and pathological features of the mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney. Methods Seven cases of MTSCC were analyzed by gross examination and light microscopy. Immunostaining was performed to detect the expression of CD10, CK7, CK18, CK19, Villin, EMA, P504S and vimentin. The literature on this tumor was reviewed to discuss the histological features of MTSCC and its clinical behavior. Results Three of 7 cases were male and the other 4 were female. The mean age of the patients was 48.2 years old, with a range from 39 to 61 years. All the patients presented no symptom and their tumors were found by health examination. Tumors averaged 5.5 cm in greatest dimension (range from 4.0 cm to 9.0 cm). The tumors were well-circumscribed without capsules, and the cut surfaces were solid and soft with white-tan color. By light microscopy, tumors were composed of tightly packed, small, elongated tubules with transitions to spindle cell components. Five cases had mucinous stroma. Clear cell clusters, focal sarcomatoid differentiation, papillations and foamy macrophages were seen in several cases. Immunohistochemically, all 7 cases showed positive for CK7, five of 5 cases positive for EMA, CK18 and P504S, four of 5 cases positive for CK19, but heterogeneous for CD10, villin and vimentin expression. No evidence of local recurrence or distant metastases was identified in the 5 patients with follow-up information. Conclusions The mucinous tubular and spindle cell carcinoma is a low-grade and polymorphic neoplasm. The morphology of these tumors may not be uniform with a wide histological spectrum. The tumors can be tubular predominant or spindle cells predominant with scant to abundant mucinous stroma, which coupled with the presence of other unusual features such as clear cells, papillations, foamy macrophages, necrosis and sarcomatoid differentiation. Immunohistochemically, MTSCC can express the markers from the proximal convoluted tubules to collecting tubules.