Clear cell papillary renal cell carcinoma and clear cell renal cell carcinoma arising in acquired cystic disease of the kidney: an immunohistochemical and genetic study

Clear cell papillary renal cell carcinoma (RCC) is a recently established disease entity. However, there are few reports on genetic study of this entity. We report such a case with focus on genetic study. A 57-year-old Japanese man was found to have 3 renal tumors. Histologically, two tumors showed findings of clear cell RCC; and the other tumor showed findings of clear cell papillary RCC that was characterized by papillary growth pattern of neoplastic cells in cystic space with purely clear cell cytology. Immunohistochemically, tumor cells of clear cell papillary RCC were diffusely positive for PAX2 and cytokeratin 7, but negative for CD10, RCC Ma, and AMACR. In fluorescence in situ hybridization study for one clear cell papillary RCC, we detected polysomy for chromosome 7 and monosomy for chromosomes 17, 16, and 20. In addition, we detected mutation of VHL gene in clear cell RCC, but found no VHL gene mutation in clear cell papillary RCC. Finally, our results provide further evidence that clear cell papillary RCC may be both morphologically and genetically distinct entity from clear cell RCC and papillary RCC.     

Renal cell carcinoma in acquired cystic kidney disease

Yakirevich E, Sabo E, Klorin G, Alos L, Cardesa A, Ellis G L, Shumway B S & Gnepp D R
(2010) Histopathology 57, 395–409
Primary mucin‐producing tumours of the salivary glands: a clinicopathological and morphometric study Aims: To determine clinicopathological and morphometric features that discriminate between mucin‐producing primary salivary gland carcinomas. Materials and results: Fifteen mucin‐producing tumours were stratified into five colloid carcinomas (CCs), four mucinous cystadenocarcinomas (MCAs), three mucin‐rich salivary duct carcinomas (SDCs) and three mucin‐rich mucoepidermoid carcinomas (MECs). The mean patient age was 70, 58, 43 and 63 years for CC, MCA, SDC and MEC, respectively. Eleven of 15 patients were female. The majority of CC cases originated from major salivary glands; MCA showed a predilection for the minor salivary glands. No disease‐related mortality was observed in the CC group; one patient died in the MCA group, and one in the SDC group. Receiver–operating characteristic curve analysis revealed an optimal cut‐off point of 17% of the tumour cells in contact with stroma that best distinguished between the CC and MCA. Histomorphometric measurements revealed that CC was best differentiated from MCA by smaller nuclear size and more regular chromatin. Conclusions: Strict morphological criteria of CC coupled with assessment of the tumour cell/stroma relationship and the nuclear features facilitate discrimination between mucinous tumours of salivary gland.     

Endocrine pancreas in cystic fibrosis: an immunohistochemical study

The pancreases of 17 patients who had cystic fibrosis with and without diabetes mellitus were evaluated at autopsy by routine staining and immunohistochemical methods for insulin, glucagon, somatostatin, and pancreatic polypeptide. Qualitative assessment of the number of islets of Langerhans and the degrees of exocrine pancreatic atrophy, fibrosis, and fat replacement was made for each pancreas. Quantitative assessment of islet composition was performed in 15 of the 17 based on the immunochemical reactivity of each cell type. Nondiabetic patients with cystic fibrosis in the latter part of the first decade of life have classic fibrocystic changes of the pancreas, with some persisting exocrine tissue, islets that appear normal, and prominent nesidioblastosis. The latter process may protect these patients from glucose intolerance. Young adult diabetic patients with cystic fibrosis have total loss of exocrine pancreas with fat replacement, lack of nesidioblastosis, a qualitative decrease in the number of islets, fibrosis of and amyloid deposits in islets, decreased numbers of insulin-containing cells in each islet, and atrophy of islet cells, probably resulting from progressive ischemia. Although the potential exists for an increasing incidence of diabetes mellitus in patients with cystic fibrosis as their life spans increase, individual variation occurs in this disease.     

Histogenesis of stromal cells in cerebellar hemangioblastomas. An immunohistochemical study.

Fifteen cerebellar hemangioblastomas were examined by immunohistochemistry for expression of neuron-specific enolase (NSE) and various neuropeptides using the avidin-biotin-complex peroxidase reaction with the following antibodies: NSE, synaptophysin, serotonin, substance P, vasoactive intestinal peptide (VIP), neuropeptide YY, neurotensin, and leu-enkephalin. In all tumor biopsies most of the stromal cells were positive for NSE. About 30% of the stromal cells showed a weak cytoplasmic synaptophysin positivity. Approximately 25% of the stromal cells were labeled with antibodies against substance P and neuropeptide YY. The partly strong reactivity was localized preferentially in perinuclear regions. These positive cells were mainly distributed in small cell clusters but were also scattered in the tumor parenchyma. In all tumor biopsies scattered cells exhibited strong perinuclear enkephalin positivity, corresponding probably to mast cells, whereas stromal cells were entirely negative. For serotonin, VIP, and neurotensin no specific reaction was seen. On the basis of these findings it is proposed that hemangioblastomas have a neuroendocrine component.     

Sarcomatoid collecting duct carcinoma arising in the hemodialysis-associated acquired cystic kidney: an autopsy report

A case of sarcomatoid collecting duct carcinoma (CDC) arising in a long-term hemodialysis-associated acquired cystic kidney was reported. A 71-year-old woman with a 21-year history of hemodialysis showed a peritoneal metastatic carcinoma (carcinomatous peritonitis) with an unknown primary site. An autopsy revealed a sarcomatoid collecting duct carcinoma of the right kidney with multicyst formation. In addition to the carcinomatous peritonitis, the tumor metastasized to the lymph nodes and bilateral lung. The primary tumor was composed of both carcinomatous and sarcomatous components, suggesting a high-grade transformation. Carcinomatous tumor cells were positive for epithelial membranous antigen (EMA), cytokeratin, and reactive to soybean agglutinin and peanut agglutinin, whereas the sarcomatous cells were positive for vimentin as well as EMA. Thus, the immunohistochemical and lectin-histochemical analysis confirmed that the tumor originated in the medullary collecting duct. Although CDC is not common in acquired cystic kidney disease patients, attention should be given to the occurrence of high-grade carcinoma of rare histological variant, as well as conventional renal cell carcinoma.     

Renal neoplasia and acquired cystic kidney disease in patients receiving long-term dialysis

Acquired cystic disease (ACD) is a recently described phenomenon occurring in the native kidneys of patients treated with long-term dialysis. Renal cell carcinoma is being diagnosed with increasing frequency in patients with chronic renal failure. In most, but not all, instances the cancers develop in association with ACD. Careful microscopic examination of end-stage kidneys undergoing dialysis discloses cysts lined with hyperplastic cells. Papillary hyperplasia of cyst epithelium is recorded in virtually every detailed pathology report of tumors arising in ACD and is the likely pathogenetic basis for the development of renal tumors in cystic kidneys undergoing dialysis. The pathology of ACD and its related neoplasms is reviewed. An estimate is made of the incidence of ACD and renal cell carcinoma in patients receiving dialysis by tabulating data from studies published in medical journals. Acquired cystic disease is found in approximately 35% of patients treated by long-term hemodialysis. Renal cell carcinoma occurs in approximately 5.8% of cases of ACD. Most of the cancers are found incidentally at autopsy or by examination of kidneys from bilateral nephrectomies and are of little clinical significance, but occasional cases present aggressive neoplasms that metastasize and cause the deaths of patients.     

Histogenesis of granular cell tumour--an immunohistochemical and ultrastructural study

Fifteen cases of granular cell tumour of superficial soft tissues or tongue were immunohistochemically evaluated for different types of intermediate filament proteins and for laminin, a glycoprotein of basal laminae. Four of the tumours were studied ultrastructurally. The tumour cells appeared to contain only vimentin-type of intermediate filament protein. The lobules of tumour cells were surrounded by laminin-positive material, but in contrast to schwannomas and neurofibromas, the individual tumour cells were not covered by laminin. In line with the immunohistochemical observations, by electron microscopy basal lamina-like material could not be demonstrated between individual cells, but only surrounding groups of cells. Lysozyme, a histiocytic marker, was absent in the tumour cells. Our results do not confirm any particular cell type for the histogenetic origin of granular cell tumour, but suggest that it may rather be derived from uncommitted possibly nerve-related mesenchymal cells.     

Peritoneal cystic mesothelioma: an electron microscopic and immunohistochemical study of two male patients.

The clinical, pathological, and ultrastructural features of two cases of peritoneal cystic mesothelioma occurring in men were studied. The results of immunohistochemical staining for CAM 5.2, epithelial membrane antigen, carcinoembryonic antigen, and Factor VIII related antigen are reported for the first time and compared with the staining results of two peritoneal cystic lymphangiomas. Although resembling cystic lymphangioma by light microscopy, cystic mesothelioma may have a greater tendency for local recurrence. Staining for CAM 5.2 or epithelial membrane antigen may facilitate the differentiation of these two entities.     

Hodgkin's disease: an immunohistochemical and histological study

The distribution of immunoglobulin (Ig) in Hodgkin's tissue has been demonstrated in paraffin and cryostat sections by the unlabelled antibody peroxidase-antiperoxidase (PAP) method and the two-stage fluorescein isothiocyanate (FITC)-based technique. The morphology and histogenesis of the Reed-Sternberg (RS) and Hodgkin (HD) cells has been studied with the metalophil method of Marshall (1948) and this revealed a population of dendritic histiocytes which corresponded in number, sizes and distribution to the RS and HD cells in adjacent sections stained by haematoxylin and eosin. The largest RS cells, however, appeared to be non-dendritic. A notable feature of Hodgkin's tissue was the tendency for the dendritic cells to form "nodules", in combination with a population of small lymphocytes. The PAP technique reveals Ig in the form of mu and delta heavy chains, as well as kappa and lambda light chains, in close association with and probably on the surface of a high proportion of these lymphocytes, suggesting that they are immature B cells. Similar reactions were given by the mantle of lymphocytes of surviving normal lymphoid follicles, and metalophil dendritic histiocytes were also demonstrated within the mantle and subjacent part of the germinal centre. Numerous immunocytes containing Ig were present in all lesions; in the majority of cases, more cells contained gamma than alpha or mu heavy chains, although in these cases alpha-positive cells outnumbered those containing gamma or mu heavy chains. In two-thirds of the cases, one-third of the RS cells contained cytoplasmic immunoglobulin. This was exclusively gamma heavy, although both light chains were present. In about half the cases a minority of the HD cells contained gamma chain. The results suggest that HD and RS cells are dendritic histiocytes of the type normally found in the lymphoid follicles and that their tendency to form nodules in assoication with B lymphocytes is a manifestatin of this origin. It is suggested that the presence of Ig most probably results from absorption of antigen-antibody complexes on the cell surface.     

Acquired cystic disease-associated renal tumors: an immunohistochemical and fluorescence in situ hybridization study.

End-stage renal disease is associated with an increased incidence of renal cell neoplasms. Among these, recent studies have identified tumors with unusual histological patterns that do not fit into the categories recognized in the current classification system. These tumors often occur in kidneys with acquired cystic disease and are composed mainly of large eosinophilic cells arranged in solid, cribriform, acinar, or papillary patterns. They also contain deposits of calcium oxalate crystals. We investigated three eosinophilic epithelial tumors arising in kidneys with acquired cystic disease from three patients. Each of the tumors was composed of large eosinophilic cells arranged in solid, acinar, or tubulocystic architecture. Deposits of calcium oxalate crystals were present in each tumor. Hale's colloidal stain showed a positive cytoplasmic reaction in one of the neoplasms. Immunohistochemistry displayed positive results for CD10 (3/3), AE1/AE3 (3/3), alpha-methylacyl-CoA racemase (2/3), CAM5.2 (2/3), and vimentin (1/3). Reactions for epithelial membrane antigen, cytokeratin 7, and high molecular weight cytokeratin (34betaE12) were negative. Fluorescence in situ hybridization analysis showed no losses or gains of chromosomes 1, 2, 6, 10, or 17 in one tumor. There were gains of chromosomes 1, 2, and 6 in two tumors. One of these tumors also showed gains of chromosome 10. Eosinophilic renal cell tumors associated with acquired cystic disease have immunophenotypes and genetic profiles distinct from the renal cell neoplasms recognized in the current classification of renal cell neoplasia, and should be considered as a distinct clinicopathologic entity in the spectrum of renal cell neoplasia.     

Histogenesis of the renal cysts in adult (autosomal dominant) polycystic kidney disease: a histochemical study

We studied the kidneys from ten patients with adult (autosomal dominant) polycystic kidney disease (APKD) stained with lectins specific for different segments of the nephron on 20 cysts from each case (ranging in size from 0.1 to 1.3 cm in nine cases and from 1.5 to 6 cm in one case). The epithelium of all cysts with positive reactivity (Arachis hypogaea and epithelial membrane antigen) was of collecting duct origin. Many cysts remained unstained. Cysts of proximal tubule origin could not be identified using the specific lectin Lotus tetragonolobus. Focal epithelial hyperplasia appeared in the collecting duct cysts. Cysts surrounded by smooth muscle were frequent and considered to be of collecting duct origin. One case had glomerular cysts. We conclude that the cysts of APKD are principally of collecting duct origin.     

Glomerulocystic kidney disease in a Belgian Malinois dog: an ultrastructural, immunohistochemical, and lectin-binding study

Renal cysts in the cortex of a juvenile Belgian Malinois dog with acute renal failure were studied by means of light, scanning and transmission electron microscopy, immunohistochemistry for intermediate filaments, and binding for wheat germ agglutinin (WGA), peanut agglutinin (PNA), and Maclura pomifera agglutinin (MPA) lectins to determine the morphological and histochemical features of the epithelial cells of these cysts. The cysts were renal corpuscles with expanded urinary space. Glomerular tufts were small with poorly developed capillary loops and increased mesangial matrix. Continuity with the proximal tubule was evident in some cystic glomeruli. Two cell types lined Bowman's capsule. One was squamous with a central cilium and microvilli. The other had morphological and histochemical features of immature podocytes (parietal podocytes). These cells were round and protruded into the urinary space; they had thick cytoplasmic projections that resembled foot processes of podocytes, microvilli, and filtration slits. The parietal podocytes expressed vimentin and cytokeratins and had affinity for WGA as do normal immature podocytes. These features suggest that the parietal podocytes are derived by metaplasia of the parietal cells. The basement membrane of Bowman's capsule was irregularly thickened and showed multifocal glycosylation changes with lectin histochemistry (WGA, PNA, MPA) in areas adjacent to the parietal podocytes. Histologic and ultrastructural findings in this dog are consistent with glomerulocystic kidney disease. This is the second report of canine glomerulocystic kidney disease. Features are similar to those of the human counterpart, but it is unclear whether genetic defects cause the disease in the dog. The presence of parietal podocytes in all cysts suggests that abnormal differentiation may play an important role in the pathogenesis of this type of polycystic kidney disease.     

Clear cell sarcoma of the kidney. An immunohistochemical study

Three cases of clear cell sarcoma of the kidney (CCSK) and 5 cases of Wilms' tumor were investigated immunohistochemically to examine the expression of tissue-specific intermediate filaments (cytokeratin, vimentin, and desmin) and myoglobin. In CCSK, tumor cells were negative for cytokeratin, except for occasional tubular structures, and vimentin was demonstrated in only one case. In Wilms' tumor, epithelial components were positive for cytokeratin and stromal cells were positive for vimentin, while no staining was found in blastemal cells for either. Both desmin and myoglobin were negative in all tumor cells except for skeletal muscle cells in Wilms' tumor. In the current study, some neoplastic cells in CCSK were revealed to be of mesenchymal nature, but blastemal cells in Wilms' tumor were not.     

Zebrafish pronephros: a model for understanding cystic kidney disease.

The embryonic kidney of the zebrafish is the pronephros. The ease of genetic analysis and experimentation in zebrafish, coupled with the simplicity of the pronephros, make the zebrafish an ideal model system for studying kidney development and function. Several mutations have been isolated in zebrafish genetic screens that result in cyst formation in the pronephros. Cloning and characterization of these mutations will provide insight into kidney development but may also provide understanding of the molecular basis of cystic kidney diseases. In this review, we focus on the zebrafish as a model for understanding cystic kidney disease and the links between cystic kidney disease and left-right patterning.     

Multicystic structures appearing in mature cystic teratomas of the ovary: an immunohistochemical and ultrastructural study

Multicystic or sieve-like areas are frequently present in the walls of mature cystic ovarian teratomas. This histological, immunohistochemical and ultrastructural study supports the contention that such cysts arise from oleous material which has been extravasated through the cyst wall and become lodged within fibrous tissue and small blood vessels. Some cysts may also arise from degenerate sebaceous glands.     

Ovarian-type stroma in hepatobiliary cystadenomas and pancreatic mucinous cystic neoplasms: an immunohistochemical study

We compared immunohistochemical expression of hepatocyte growth factor (HGF), c-met, alpha-inhibin, estrogen receptor (ER), and progesterone receptor (PR) in 10 pancreatic mucinous cystic neoplasms (PMCNs), 8 hepatobiliary cystadenomas (HBCs), and 6 simple liver cysts (SLCs).All HBCs and PMCNs were in women (mean ages, 45.7 and 54.9 years, respectively; P > .05). All HBCs had abundant stroma; PMCN stromal density was more variable (score, 3.0 vs 1.8; P < .05). Stroma in HBCs had greater ER and PR staining (both P < .05) and more consistent, focal, strong reactivity for alpha-inhibin than PMCNs (P < .05). SLCs were found in men and women, lacked ovarian-type stroma, and were negative for ER, PR, and alpha-inhibin. HGF expression was not significantly different in the epithelium of HBCs, PMCNs, and SLCs; c-met expression in the epithelium of HBCs and PMCNs was significantly stronger than in SLCs (P < .05).Differences in stromal density and ER, PR, and alpha-inhibin immunoreactivity in HBCs and PMCNs suggest that different hormonal environments in the liver and pancreas contribute to stromal variation. Up-regulation of c-met in HBCs and PMCNs suggests c-met activation in the pathogenesis of pancreaticobiliary cystic neoplasms.     

Somatic von Hippel-Lindau disease gene mutation in clear-cell renal carcinomas associated with end-stage renal disease/acquired cystic disease of the kidney

It has been documented that renal cell carcinomas (RCCs) occur frequently in patients treated with long-term dialysis, especially in cases of end-stage renal disease (ESRD)/acquired cystic disease of the kidney (ACDK). To address the molecular pathogenesis of ESRD/ACDK-associated RCCs, we examined 14 RCCs (7 clear-cell and 7 papillary carcinomas) in patients receiving dialysis for somatic mutations of the von Hippel-Lindau disease (VHL) gene as well as of the tyrosine kinase domain of the MET oncogene. Direct sequencing analyses revealed that three tumors exhibited VHL frameshifts (618delA, 386-395del10-bp, and 723-724insTC). One of the VHL mutated tumors showed additional loss of heterozygosity at the VHL gene locus. Histopathologic and clinical data demonstrated that the three tumors having VHL mutations were clear-cell RCCs occurring in ESRD with 55, 106, and 156 months of dialysis history, respectively. We did not find any tumors with mutations in the tyrosine kinase domain of the MET. These results demonstrated that the VHL tumor-suppressor gene is also involved in a subset of clear-cell RCCs occurring in ESRD/ACDK, as in the case of sporadic clear-cell RCCs. However, mutations of the MET oncogene could not be found in the seven ESRD/ACDK-associated papillary RCCs examined.     

Hepatoblastomas: an ultrastructural and immunohistochemical study.

Seven hepatoblastomas were studied by electron microscopy, and four of these were studied by immunohistochemistry. Five tumors were purely epithelial, and two were mixed epithelial-mesenchymal. They showed a spectrum of cellular differentiation ranging from primitive epithelial cells to differentiated cells resembling adult hepatocytes. Glycogen, lipid, basal lamina, and canaliculi were present in all cases. Mitochondria with large, membrane-bound, amorphous inclusions were present in one tumor, and large, complex, basal cell processes were present in two tumors. Ultrastructural features most characteristic of hepatocytes were most common in fetal type hepatoblastomas. Immunoreactive chromogranin cells were present in two tumors, one of which also contained immunoreactive somatostatin cells. The somatostatin-positive tumor had cells with granules resembling those seen in somatostatin-containing cells of normal pancreas and somatostatin-containing neuroendocrine carcinomas. Other immunoreactive substances were present, including alpha 1-antitrypsin (four cases), vimentin (embryonal cells in four cases; fetal cells in three cases), low-molecular weight cytokeratin (embryonal cells in three cases; fetal cells in four cases), and high-molecular weight cytokeratin (embryonal cells in one case; fetal cells in two cases). Osteoidlike material was positive for epithelial membrane antigen, vimentin, and S-100 protein.     

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.     

Renal cell carcinoma with intratumoral calcium oxalate crystal deposition in patients with acquired cystic disease of the kidney

We describe 2 cases of renal cell carcinoma arising in acquired cystic disease of the kidney (ACDK) in patients with end-stage renal disease undergoing hemodialysis for more than 5 years and provide a brief review of the complications of ACDK. In both cases, abundant calcium oxalate crystals were observed within the tumors. Histologically, one of the tumors was a conventional (clear cell) renal cell carcinoma. The other tumor was a bilateral papillary renal cell carcinoma. Both tumors were high-grade carcinomas with extensive oncocytic (acidophilic) features. Also noted within the kidneys were cysts with atypical papillary hyperplasia. The clinicopathologic findings along with review of the literature suggest a relationship between tumor growth and calcium oxalate crystal deposition in patients undergoing hemodialysis with ACDK.