Differential expression of type 2 3α/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) in tumors of the central nervous system

Human aldo-keto reductase (AKR) 1C3, type 2 3α-hydroxysteroid dehydrogenase (HSC)/ type 5 17β-HSD, is known to be involved in steroids, prostaglandins, and lipid aldehydes metabolism. The expression of AKR1C3 has been demonstrated in hormone-dependent normal tissues such as breast, endometrium, prostate, and testis; and de -regulated AKR1C3 expression has been shown in breast carcinoma, endometrial hyperplasia, endometrial carcinoma, and prostate carcinoma. AKR1C3 expression has also been demonstrated in hormone-independent normal tissues (renal tubules and urothelium) and neoplastic tissues (renal cell carcinoma, Wilm's tumor, and urothelial cell carcinoma). Extensive expression of AKR1C3 in normal and neoplastic as well as hormone-dependent and hormone-independent tissues indicates that AKR1C3 may have functions beyond steroid hormone metabolism. In this report, we describe a widespread expression of AKR1C3 in glial neoplasms and meningiomas, with limited expression in medulloblastoma and no expression in Schwannoma. These tumors, except meningioma, are not classically considered to be sex hormone-dependent or related brain tumors. The current results corroborate our earlier observations that AKR1C3 is expressed in both sex hormone-dependent and hormone-independent malignancies. Similar to AKR1C3 distribution in Wilm's tumor, we also demonstrate that expression of AKR1C3 is reduced in tumors with embryonic phenotypes.     

Suppressed expression of type 2 3��/type 5 17��-hydroxysteroid dehydrogenase (AKR1C3) in endometrial hyperplasia and carcinoma

The diagnosis of endometrial hyperplasia and endometrial type adenocarcinoma arising within the uterine cavity has long been rested on morphologic criteria. Although distinction between normal endometrial epithelium from adenocarcinoma is usually straightforward, the separation between normal and hyperplastic endometrium, particularly those cases without atypia, can be a diagnostic challenge. The same is true in separation of hyperplastic endometrium with atypia from endometrial-type endometrial adenocarcinoma. Type 2 3α-/type 5 17β-hydroxysteroid dehydrogenase (HSD) (AKR1C3) is a multifunctional enzyme involved in androgen, estrogen, progesterone, and pros-taglandin metabolism. Its expression has been shown in the epithelium of the renal tubules, urothelial epithelium, and endothelial cells in normal tissues as well as in prostatic adenocarcinoma. The proliferation and maintenance of endometrial epithelium is dependent on both estrogen and progesterone; and AKR1C3-mediated steroid metabolism may play a critical role in the maintenance of viable normal and abnormal endometrial epithelium. We studied the expression of AKR1C3 in 33 endometrial biopsy specimens including 13 cases of normal proliferative endometrium, 8 cases of hyperplastic endometrium with and without atypia, and 12 cases of primary endometrial adenocarcinoma of endometrial type. We demonstrated a uniform, diffuse, and strong expression of AKR1C3 in normal endometrial epithelium but not in endometrial stromal cells. In contrast, the expression of AKR1C3 is reduced in both hyperplastic and carcinomatous endometrial epithelium. These findings suggest that AKR1C3 may play important roles in the physiology of endometrial cells and that suppressed AKR1C3 expression may represent a feature that allows differentiation of hyperplastic and neoplastic endometrial epithelium from normal endometrial epithelium. However, reduced AKR1C3 expression cannot distinguish hyperplastic endometrium from endometrial adenocarcinoma of endometrial type. The biologic and pathological roles of AKR1C3 in endometrial epithelium require further investigation.     

Aldo-keto reductase family 1 member C3 (AKR1C3) is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma

Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids including estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin reductase activity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endometrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demonstrated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junction. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunoreactivity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma pathogenesis require further studies.     

Polycystic kidney disease in SBM transgenic mice: role of c-myc in disease induction and progression.

SBM mouse is a unique transgenic model of polycystic kidney disease (PKD) produced by dysregulation of c-myc in the kidneys. Our previous demonstration that c-myc is overexpressed in human autosomal polycystic kidney disease (ADPKD) prompted us to investigate the pathogenetic role of c-myc in the induction and progression of the cystogenic phenotype in our mouse model. In young SBM kidneys, c-myc was two- to threefold increased with persistent expression levels into adulthood, an age when c-myc is normally undetectable. In situ hybridization analysis of the c-myc transgene demonstrated intense signal specifically overlying glomerular and tubular epithelium of developing cysts in fetal and young kidneys. Increased expression of c-myc correlated with the initiation and progression of the PKD phenotype as evidenced by early tubular and glomerular cysts at E16.5. Cyst number and size increased with age, with co-development of glomerular and tubular epithelial hyperplasia. Consistently, the mean renal proliferative index was increased approximately 5- to 20-fold in noncystic and cystic tubules of newborn SBM animals compared with littermate controls. Similarly, in fetal and newborn kidneys the tubular apoptotic indices were increased approximately three- to ninefold over controls. Both proliferation and apoptotic rates in cystic tubules approached levels in developing tubules from the normal nephrogenic zone. We conclude that the pathogenesis of PKD hinges on a critical imbalance in c-myc regulation of the opposing processes of cell proliferation and apoptosis, recapitulating the cellular phenomena in developing fetal kidney.     

An immunophenotypic comparison of metanephric metaplasia of Bowman capsular epithelium with metanephric adenoma, Wilms tumor, and renal development: a case report and review of the literature

Metanephric metaplasia of the parietal epithelium of the Bowman capsule is a rare pathologic finding of unknown pathogenesis that has occurred in patients with widespread malignant neoplasms of various types. We report this finding in a 25-year-old woman with partial expression of the Carney triad who died of a disseminated gastrointestinal stromal tumor, specifically a gastric stromal sarcoma. The metaplasia involved both kidneys diffusely. It originated in the parietal epithelium of the Bowman capsule, extended into the proximal tubules, and focally surrounded the glomeruli in a semicircular manner Immunohistochemical analysis revealed that the cells of metanephric metaplasia expressed the Wilms tumor gene product, bcl-2 protein, and CD57 and cytokeratin 7 and keratin AE1/AE3 focally, but not CD56. This immunophenotype parallels that of metanephric adenoma, Wilms tumor, and nephrogenic rests and overlaps with antigen expression in certain periods of renal development.     

Collecting duct carcinoma of the kidney: an immunohistochemical evaluation of the use of antibodies for differential diagnosis

Collecting duct carcinoma is a highly aggressive renal epithelial malignancy, although it accounts for less than 1% of the incidence of renal epithelial neoplasms. Differential diagnoses between collecting duct carcinoma, pelvic urothelial carcinoma with marked invasion to the renal parenchyma (invasive urothelial carcinoma), and papillary renal cell carcinoma is often challenging. In our current study, we examined the utility of using commercially available antibodies, in conjunction with lectin histochemistry, for such differential diagnoses. We examined 17 cases of collecting duct carcinoma, 10 cases of invasive urothelial carcinoma and 15 cases of papillary renal cell carcinoma (type 1, 6 cases; type 2, 9 cases) in these evaluations. Our results indicated that Ulex europaeus agglutinin 1, E-cadherin, and c-KIT were frequently positive in collecting duct carcinoma and invasive urothelial carcinoma, in comparison with papillary renal cell carcinoma, which had negative results for CD10 and α-methylacyl CoA racemase. We found, however, that collecting duct carcinoma showed positivity for high-molecular-weight cytokeratin and low-molecular-weight cytokeratin at a low frequency compared with invasive urothelial carcinoma, and that these distinctions need further careful evaluation. In addition, high-molecular-weight cytokeratin positivity was not a reliable marker for collecting duct carcinoma. We conclude that Ulex europaeus agglutinin 1 reactivity and positivity for E-cadherin and c-KIT are effective in distinguishing collecting duct carcinoma from papillary renal cell carcinoma, and that negative results for α-methylacyl CoA racemase and CD10 are potentially useful hallmarks of this distinction also. In contrast, a differential diagnosis for collecting duct carcinoma and invasive urothelial carcinoma will require careful examination of multiple routinely stained specimens, particularly in cases of in situ neoplastic lesions in the pelvic mucosa.     

End-stage kidney disease: gains of chromosomes 7 and 17 and loss of Y chromosome in non-neoplastic tissue

The aim of this study was to determine the copy number changes of chromosomes 7, 17, 3p, and Y in a non-neoplastic tubular epithelium in end-stage kidney disease (ESKD). Seventeen kidneys from 11 patients with ESKD were retrieved from the archive files. Non-neoplastic kidney tissue in these cases was examined separately. Tissues containing papillary adenomas (PA), clear (CRCC) and papillary renal cell carcinomas (PRCC), and myxoid liposarcoma (LPS) were examined using the same probes and compared with non-neoplastic tissue. Tubular changes in the kidney parenchyma were classified into three types: (1) The vast majority of tubules were entirely atrophic; (2) Several tubules were hyperplastic, i.e., tubules with undifferentiated large epithelial cells, in which it was impossible to establish the specific type of a renal tubulus; (3) Dysplastic tubules were dilated, sometimes wrinkled. The basal membranes were lined by large eosinophilic epithelial cells with polymorphic nuclei and pseudostratification. Nucleoli were clearly visible. These tubular changes were multifocal with a haphazard distribution within the atrophic parenchyma. PA were detected in nine patients, of whom eight patients also revealed an additional tumor type(s) (4x CRCC, 3x PRCC, 1x PRCC, and CRCC). One patient had a CRCC only, another had a combination of PRCC and LPS. Chromosomal abnormalities were found in the second and third group of tubular changes, i.e., in hyperplastic and dysplastic tubules. Trisomy of chromosome 7 was detected in six cases, whereas trisomy of chromosome 17 in eight cases. A combination of both trisomies was found in five cases. Loss of chromosome Y was found in two cases. Fluorescence in situ hybridization on tissues containing papillary adenomas, renal cell carcinomas, and liposarcoma revealed expected results, i.e., trisomy of chromosomes 7 and 17 in all PAs and PRCC. No gains were present in CRCC and LPS. Loss of Y was found in six PA, five PRCC, and one LPS; loss of X was found in two CRCCs. We suggest that chromosomal changes typical of the papillary renal cell lesions, i.e., trisomies of chromosomes 7 and 17, are very frequent in non-neoplastic parenchyma of the end-stage kidney, and they have a tendency to a multifocal occurrence.     

Sex,Collagen Expression,and Anterior Cruciate Ligament Strength in Rats

Context:

Sex-specific responses to steroid sex hormones have been suggested as a potential cause for the disparate anterior cruciate ligament (ACL) injury rates between male and female athletes. Type 1 collagen (T1C) and type 3 collagen (T3C) are crucial structural components that define the ligament''s ability to withstand tensile loads. Messenger RNA (mRNA) is an important mediator of downstream collagen synthesis and remodeling, but the sex-specific mechanisms of collagen mRNA expression and ACL strength are unknown.

Objective:

To examine the influence of sex on T1C and T3C mRNA expression and mass-normalized stiffness and peak failure load in the ACLs of skeletally mature rats.

Design:

Observational study.

Setting:

Basic sciences and biomechanical testing laboratories.

Patients or Other Participants:

Nineteen 12-week-old male (n  =  9) and female (n  =  10) Sprague Dawley rats.

Main Outcome Measure(s):

We used real-time polymerase chain reaction to determine T1C and T3C mRNA expression and a hydraulic materials testing device to measure ACL stiffness and failure load. Nonparametric Wilcoxon rank sum tests were used to compare the groups.

Results:

Female rats had lower amounts of T3C mRNA expression and higher normalized ACL tangent stiffness and failure load than male rats.

Conclusions:

These findings suggest that sex-specific differences in T1C and T3C mRNA expression may play an important role in the downstream mechanical properties of the ACL.     

Acute kidney injury in human leptospirosis: an immunohistochemical study with pathophysiological correlation

Tubulointerstitial nephritis is a common clinicopathological finding in leptospirosis. Clinically, nonoliguric acute kidney injury (AKI), hypokalemia, sodium, and magnesium wasting frequently occur in leptospirosis. The exact mechanisms of renal involvement remain largely unclear. Immunohistochemistry to detect expression of the endogenous sodium/hydrogen exchanger isoform 3 (NHE 3), aquaporin 1 and 2, α-Na⁺K⁺ATPase, and sodium–potassium–chloride cotransporter in its NKCC2 isoform was performed on kidneys removed during autopsy of human leptospirosis cases and kidneys removed during autopsy of human non-leptospirosis cases with and without evidence of acute tubular necrosis (ATN). A decrease in NHE 3, aquaporin 1, and α-Na⁺K⁺ATPase expression occurred in proximal convoluted tubule cells. Expression of aquaporin 1 was preserved along the descending thin limb of the loop of Henle in the outer medulla. α-Na⁺K⁺ATpase expression was essentially preserved in the distal tubules, i.e., the thick ascending limb of the loop of Henle, macula densa, and distal convoluted tubule. Aquaporin 2 expression in the collecting tubules was enhanced compared to those of non-leptospirotic kidneys. NKCC2 cotransport isoform was expressed in the thick ascending limb of the loop of Henle and was essentially preserved in leptospirotic kidneys. Primary injury of the proximal convoluted tubules is regarded as the hallmark of the kidney in leptospirosis. Sodium and water transport are particularly affected with increased distal potassium excretion, hypokalemia, and polyuria. Enhanced expression of aquaporin 2 in medullary collecting tubules is probably an attempt to retain water during the nonoliguric phase of renal failure.     

CD2-associated protein in human urogenital system and in adult kidney tumours

We studied expression of CD2-associated protein (CD2AP) in human urogenital system and in adult kidney tumours. In the cortex of normal kidney, CD2AP was expressed in all types of tubules and in the glomeruli. Labelling was more intense in cytokeratin 7- and in Tamm–Horsfall-positive tubules than in proximal tubules. In the medulla, expression was observed in the collecting ducts. Urothelium and the epithelium of prostatic acini, seminal vesicles, seminiferous tubules, epididymal ducts, Fallopian tube, endometrium and endocervix as well as granulosa cells showed moderate to strong CD2AP positivity. In syncytiotrophoblast, the expression was weaker than in cytotrophoblast. Endometrial stroma was negative, but decidualised stroma was weakly positive. Clear cell renal cell carcinoma (RCC) (n=63) showed a weak expression. Type-I papillary RCCs (n=4) and papillary adenomas (n=3) were negative. The epithelium lining the cysts in multilocular cystic RCCs (n=3) and in cystic nephroma (n=1) was strongly positive. Chromophobe RCCs (n=2), oncocytomas (n=3) and urothelial carcinomas (n=2) were moderately positive. The results show that CD2AP displays a specific expression pattern in human urogenital organs and that distinct expression is shown in several types of kidney tumours but not in type-I papillary RCCs or in papillary adenomas.     

Renal cystic neoplasms and renal neoplasms associated with cystic renal diseases: pathogenetic and molecular links

Cystic renal neoplasms represent an isolated cystic mass not accompanied by cystic change of the renal parenchyma. Although cystic change may be seen in any type of renal neoplasm, a few (i.e., cystic renal cell carcinoma, cystic nephroma, cystic partially differentiated nephroblastoma, mixed epithelial and stromal tumor) are characterized by constant cystic change that may involve the entire tumor. Cystic kidney disease is characterized by cystic change, which usually involves the kidneys in a bilateral and diffuse pattern, does not create a discreet mass, and is due to hereditary or developmental conditions. Some of the cystic kidney diseases are not known to give rise to renal neoplasm; others such as autosomal polycystic kidney disease or multicystic dysplastic kidney may fortuitously coexist with renal neoplasms. Three conditions (acquired cystic kidney disease, tuberous sclerosis, and von Hippel-Lindau disease) are associated with renal neoplasms with such a high frequency that they are considered preneoplastic. This article reviews the differential diagnoses among cystic neoplasms. It also focuses on the underlying genetic and molecular mechanisms for the relationship between cystic renal diseases and renal neoplasms.     

Vimentin metaplasia in renal cortical tubules of preneoplastic, neoplastic, aging, and regenerative lesions of rats and humans.

Vimentin expression was studied immunohistochemically in renal cortical tubules of untreated male rats of various ages, rats exposed to toxins (barbital sodium, folic acid) and carcinogens (streptozotocin, N-bis(2-hydroxypropyl)nitrosamine, barbital sodium, and in humans of various ages with or without renal epithelial tumors. Fetal, neonatal, and young adult rats did not express vimentin in renal cortical tubules. Regenerative renal tubular lesions from rats with aging nephropathy and from rats with toxic nephropathy both expressed vimentin. Mitogenic lesions induced by folic acid at 24 hours, however, were not immunoreactive for vimentin. Carcinogen-induced preneoplastic renal cortical tubular lesions in rats were most often focally immunoreactive whereas strong vimentin expression was found in almost all induced renal tumors. In kidneys of three children (younger than 2 years of age), vimentin was not found in renal cortical tubular cells except in rare individual cells in one case. Vimentin was abundant in basophilic regenerative tubules in kidneys of aged individuals, however. Most (7/10) human renal carcinomas and latent preneoplastic or neoplastic renal tubular lesions found incidentally at autopsy (2/4) showed vimentin expression. The authors suggest that the switching to vimentin expression in phenotypically normal renal cortical tubular cells in rats and humans, which do not usually express the intermediate filament protein vimentin, should be considered vimentin metaplasia. Vimentin expression is dissociated from increased cell proliferation in hyperplastic and neoplastic lesions, however. Instead the degree of dedifferentiation of the tubule cells and changes in phenotype were associated with vimentin expression.     

Expression of intermediate filament proteins in fetal and adult human kidney: modulations of intermediate filament patterns during development and in damaged tissue.

The expression of intermediate filament proteins, particularly individual cytokeratins (CKs), vimentin, and glial filament protein, was immunohistochemically investigated using frozen sections and Carnoy-fixed, paraffin-embedded tissue from normal fetal and adult human kidneys as well as from pathologically altered kidneys. In fetal kidneys, the co-expression of CKs and vimentin was detected in the visceral and parietal epithelium of the glomerulus, the proximal tubules, the thin loops of Henle, and the collecting ducts. In contrast, in the tubules of normal adult kidneys, the presence of vimentin and CKs was nearly always mutually exclusive. While CKs 8 and 18 were present in all tubular epithelia, CKs 19 and 7 each exhibited a distinctive distribution pattern, there being a striking alteration between positive and negative segments and, not infrequently, intratubular heterogeneities. In certain segments, particular cell types (e.g., "plica cells," intercalated cells) could thus be recognized. In tubular epithelia altered by various injurious conditions, novel or enhanced expression of vimentin, CK 19 and CK 7, and, less frequently, CK 17 and glial filament protein was noted in certain segments. The increase in intermediate filament protein expression in altered (particularly proximal) tubules appeared to parallel the reduction in the degree of differentiation. Vimentin was never detected in distal tubules. The present results reveal a considerable similarity between the intermediate filament patterns in non-neoplastic proximal tubules of fetal and damaged kidney tissue and those in clear-cell and chromophilic renal cell carcinomas. They also serve to illustrate that the analysis of both fetal development and reactive cell changes may significantly contribute to our understanding of differentiation phenomena in malignant tumors.     

细胞内吞受体megalin 和cubilin在胚胎期小鼠肾的表达

目的 研究细胞内吞受体megalin和cubilin在胚胎发生发育小鼠肾的表达,及其与肾小管发生发育的相关性. 方法 采用免疫组织化学方法 检测不同胚龄小鼠肾(每组5只)megalin和cubilin的表达.同时,结合透射电镜观察肾近端小管与细胞内吞功能相关的细胞器的发育变化. 结果 胚龄9.5d时,megalin和cubilin表达于中肾管及中肾小管上皮细胞游离面.胚龄11d至18d,两受体表达于输尿管芽上皮细胞游离面,在S小体期肾小管近腔面呈弱阳性表达,肾小管胞内吞体及溶酶体少见,微绒毛稀疏.随着近髓肾单位细胞内吞体及微绒毛发育成熟,两受体表达局限于近端小管近腔面及刷状缘. 结论 megalin和cubilin 在胚胎肾发生发育中,从表达在分化早期所有小管近腔面胞质,到局限于成熟期近端小管游离面刷状缘,提示两受体协同重吸收功能是随着近端小管上皮细胞的发育而逐渐形成的.     

Collecting duct carcinoma: an entity to be redefined?

Collecting duct carcinomas (CDCs) are highly aggressive tumors with poor survival at 1 year and are often metastatic at the time of diagnosis. It has been shown that patients may have better survival when treated with a chemotherapy regimen used for urothelial carcinoma. Such tumors must therefore be recognized, but their pathological diagnosis remains difficult. The two main differential diagnoses are renal pelvis urothelial carcinoma with infiltration of the kidney and/or high-grade and high-stage papillary renal cell carcinoma. The aim of our study was to compare the immunophenotype of 14 CDCs with 6 renal pelvis urothelial carcinomas (RPUC) infiltrating the medulla. The following markers were evaluated: ulex europeus aglutinin (UEA), peanuts aglutinin, vimentin and aquaporin 3 (AQP-3), a membrane component of normal collecting duct and urothelial cells. We were able to define a reproductive urothelial phenotype AQP-3+, vimentin– and UEA+. Among the 14 CDCs, 10 cases demonstrated this immunophenotype. It coincided with an urothelial-like trabecular and tubular pattern. In contrast, the 4 remaining papillary CDCs had the inverse pattern, AQP-3–, vimentin+ and UEA–. These results suggest that: (1) the trabecular and tubular variant of CDC with the urothelial AQP-3+, vimentin– phenotype can be included in the spectrum of urothelial diseases; (2) the papillary variant probably does not belong to the same entity; (3) AQP-3 is a marker of interest for improving the histological classification of CDC and unclassified aggressive renal tumors.     

Expression of aldo-keto reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas,gastrointestinal tract,and lung

Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.     

Microcystic urothelial cell carcinoma with neuroendocrine differentiation arising in renal pelvis. Report of a case

Microcystic urothelial cell carcinoma is a rare variant of urothelial cell carcinoma which occurs in the bladder and, rarely, in the renal pelvis. Neuroendocrine differentiation is uncommon in pure urothelial carcinoma and is more frequently found in neoplasms with glandular differentiation. We report a case of microcystic urothelial cell carcinoma arising in renal pelvis and showing focal neuroendocrine differentiation. A 55-year-old man with a history of non-small cell cancer of the lung presented with abdominal pain and hematuria. Imaging studies and gross examination revealed a partially cystic mass in the left kidney. Microscopic examination disclosed invasive carcinoma with prominent microcystic features, with microcysts lined by low columnar and flat cells. Immunohistochemical analysis confirmed the urothelial histotype (positive for thrombomodulin, p63 and high-molecular-weight cytokeratins) and disclosed focal neuroendocrine differentiation.     

Expression of vimentin and cytokeratin types of intermediate filament proteins in developing and adult human kidneys

Expression of cytokeratins and vimentin in developing and adult human kidney was studied by the indirect immunofluorescence technique using monoclonal and conventional antiintermediate filament antibodies. The undifferentiated cells of the metanephric mesenchyme expressed vimentin but not cytokeratins, whereas only cytokeratins could be visualized in the cells of induced renal vesicles. At the S-shaped body stage of nephrogenesis, the presumptive visceral and parietal cells of the developing glomeruli did not contain either detectable vimentin or cytokeratins, whereas cells of the tubular pole of the S-shaped body were stained within antibodies to cytokeratins. At a later stage the cuboidal visceral epithelial cells of the presumptive glomeruli were brightly positive for vimentin, but not for cytokeratins, and maintained their expression of vimentin during later stages of glomerulogenesis and in adult kidneys. Only some of the cells of the parietal epithelium, but not other glomerular elements, showed cytokeratin-specific staining. In fetal kidneys, the epithelial cells of proximal and distal tubules and of collecting ducts showed a cytoplasmic staining with two monoclonal antibodies to cytokeratins (PKK1 and PKK2), reacting with different cytokeratin polypeptides. In adult kidneys, a basolateral fluorescence in proximal and distal tubules was obtained with PKK1 antibodies, whereas PKK2 stained only the cells of the collecting ducts. Vimentin was not found in tubular epithelial cells at any developmental stage, whereas the cells of collecting ducts showed a transient expression of vimentin in fetal kidneys. Our results show a developmental stage-dependent pattern in the expression of the intermediate filament antigens in the cells of the kidney and show the exceptional expression of only vimentin in the visceral epithelial cells of human glomeruli.