Review of chromophobe renal cell carcinoma with focus on clinical and pathobiological aspects

In recent years, the concept of chromophobe renal cell carcinoma (RCC) has been established. Chromophobe RCCs account for about 4-6% of all renal tumors. Macroscopically, the cut surface of the tumor is generally grey-beige in color. Histologically, there are two variants (typical and eosinophilic). In the typical variant, large tumor cells with architecture of a compact tubulo-cystic pattern proliferate. The cytoplasm is abundant and shows a fine reticular translucent pattern. The cell border is thick, prominent and eosinophilic. In the eosinophilic variant, tumor cells are smaller and markedly eosinophilic, and a perinuclear halo is often seen. Histochemically, the tumor cells generally show a diffuse and strong reaction for Hale's colloidal iron staining. Ultrastructurally, tumor cells contain many cytoplasmic microvesicles (150-300 nm). In chromosomal analysis, a low chromosome number is characteristic of chromophobe RCCs, due to the frequent occurrence of a combined loss of chromosomes 1, 2, 6, 10, 13, 17, and 21. In differential diagnosis, histological distinction from oncocytomas, which share a common phenotype (intercalated cells of the collecting duct system), is most important. In this diagnostic setting, recent studies have given rise to several problems. Firstly, some cases of coexistent chromophobe RCC and oncocytoma (so-called renal oncocytosis) or cases of oncocytoma with metastasis have recently been reported. Secondly, the existence of chromophobe adenoma, which is the benign counterpart of chromophobe RCC, and an oncocytic variant of chromophobe RCC has recently been suggested. Therefore, further studies are needed to elucidate the relationship between chromophobe RCCs and oncocytomas, to confirm whether chromophobe adenoma actually exists or not, and to identify the key gene that causes chromophobe RCCs.     

Review of sarcomatoid renal cell carcinoma with focus on clinical and pathobiological aspects

In sarcomatoid renal cell carcinoma (RCC), it is generally accepted that the sarcomatoid portion is derived from metaplastic transformation of carcinoma. Sarcomatoid RCCs account for about 1-8% of all renal tumors. Macroscopically, tumors generally form encapsulated masses and show invasive growth. Sarcomatoid RCCs originate from all subtypes of RCCs, including conventional, papillary, chromophobe, and collecting duct carcinomas. With regard to the growth pattern of the sarcomatoid component, malignant fibrous histiocytomatous, fibrosarcomatous and unclassified sarcomatous patterns are frequently seen. Immunohistochemically, sarcomatoid RCCs are generally positive for AE1/AE3, epithelial membrane antigen (EMA) and vimentin and negative for desmin, actin and S-100. Little is know about genetic alterations in sarcomatoid RCCs. Further studies are therefore needed to identify the key gene involved in sarcomatoid transformation of RCCs.     

Review of papillary renal cell carcinoma with focus on clinical and pathobiological aspects

Recent studies have shown that papillary renal cell carcinoma (RCC) is clinically and genotypically a distinct entity. Papillary RCCs account for about 10-15% of renal parenchymal neoplasms. Macroscopically, the cut surface is yellow or brown in color and large tumors frequently show cystic change. Hemorrhage and necrosis are common. Histologically, Delahunt and Eble have classified papillary RCCs into type 1 (small cells, single layer) and type 2 (large cells, pseudostratification) according to the cytoplasmic volume and thickness of the lining cells. In chromosomal analysis, gain of chromosomes 7 and 17, loss of Y chromosome and additional gains (chromosome 3q, 8p, 12q, 16q and 20q) are frequently found in type 1 papillary RCCs, but the chromosomal aberration of type 2 papillary RCCs seems to be more heterogenous than that of type 1 papillary RCCs. Mutations of MET proto-oncogenes in some cases of both hereditary and sporadic papillary RCCs have recently been detected. Furthermore, all hereditary and sporadic papillary RCCs with MET proto-oncogene show type 1 histological features. Type 1 papillary RCCs generally seem to have a favorable prognosis, but type 2 tumors have a worse prognosis than do type 1 tumors. Papillary RCCs with involvement of the X chromosome and cancer syndrome with predisposition to cutaneous/uterine leiomyomas and papillary RCCs, the histological features of which are basically different from those of usual papillary RCCs, have also been recently reported. Since papillary RCCs seem to constitute clinically, histologically, and even genetically more heterogenous groups than previously thought, further investigations are needed to characterize the subtype of papillary RCC.     

Review of renal oncocytoma with focus on clinical and pathobiological aspects

Renal oncocytomas account for about 3-7% of all renal tumors. Macroscopically, the cut surface of the tumor is generally mahogany brown or dark red in color. A central scar is occasionally observed. Histologically, tumor cells with finely granular cytoplasm proliferate in an edematous, myxomatous or hyalinized stroma with a nested, tubulocystic, solid or trabecular pattern. Ultrastructurally, tumor cells contain many mitochondria with lamellar cristae. Mitochondrial DNA alterations are consistently observed in renal oncocytomas. In chromosomal analysis, renal oncocytomas comprise a heterogenous group. Combined loss of chromosomes Y and 1, rearrangements affecting band 11q12-13, involvement of 12q12-13, loss of 14q, and the lack of combination of LOH at specific chromosomal sites have been reported. In differential diagnosis, the histological separation from chromophobe RCCs is of great importance. In such a setting, ultrastructural or chromosomal analysis is very useful. However, there are several findings suggesting a close relationship between chromophobe RCC and oncocytoma. First, both tumors share a phenotype of intercalated cells of the collecting duct system and mitochondrial DNA alterations. Second, some cases of coexistent oncocytoma and chromophobe RCC, designated as "renal oncocytosis", have recently been reported. Third, oncocytic variants of chromophobe RCCs that have similar ultrastructural features to those of oncocytomas have been reported. Fourth, the existence of chromophobe adenoma, which is the benign counterpart of chromophobe RCC and shows loss of chromosomes Y and 1, has recently been suggested. Finally, although almost all oncocytomas behave in a benign fashion, some cases of oncocytoma that caused metastasis or resulted in death have also been reported. Therefore, further studies are needed to resolve these problems and also to elucidate the genetic mechanisms responsible for the occurrence of oncocytomas.     

Multilocular cystic renal cell carcinoma with focus on clinical and pathobiological aspects

Multilocular cystic renal cell carcinoma (MCRCC) accounts for approximately 1 to 2% of all renal tumors. This tumor is currently classified as a subtype of clear cell RCC. Clinically, the majority of these tumors are incidentally found. Macroscopically, the tumor is well demarcated and consists of various-sized cysts. The fibrous septa are generally thin and there is no discernible expansile nodule. Microscopically, the cyst walls are lined with tumor cells with clear to occasionally slightly eosinophilic cytoplasm. The Fuhrman nuclear grade is generally low and usually corresponds to grade 1. The deletion of chromosome 3p was identified in most tumors using FISH analysis and VHL gene mutation was identified in 25% of MCRCC. As MCRCC generally exhibits a low stage of TNM classification, the great majority of these tumors have a favorable clinical course. To date, there are no reports of metastasis, vascular invasion or sarcomatoid change in MCRCC. Accordingly, nephron sparing surgery is first recommended as a therapeutic strategy.     

Review of acquired cystic disease-associated renal cell carcinoma with focus on pathobiological aspects

Acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) is a recently established entity. In this article, we introduce the general view of this new entity. Macroscopically, the disease exclusively occurs in ACD and may arise as a dominant mass or non-dominant masses. Histologically, the tumor is characterized by a microcystic pattern, neoplastic cells with an eosinophilic or oncocytic cytoplasm and frequent intratumoral oxalate crystal deposition. Prominent nucleoli of tumor cells are often observed. Immunohistochemically, neoplastic cells are generally positive for AMACR but negative for cytokeratin 7. Ultrastructurally, neoplastic cells contain abundant mitochondria in the cytoplasm. Genetically, the gain of chromosomes 3, 7, 17 and abnormality of the sex chromosome were frequently observed in several studies. In conclusion, ACD-associated RCC may be widely recognized as a distinct entity in the near future because this tumor is morphologically and genetically different from other renal tumor entities that have been previously established.     

Review of mucinous tubular and spindle-cell carcinoma of the kidney with a focus on clinical and pathobiological aspects

Recently, the characterization of mucinous tubular and spindle-cell carcinoma (MTSCC) has been established. MTSCC predominantly occurs in females. This tumor is histologically characterized by eosinophilic cytoplasm, elongated and anastomosing tubules, myxomatous stroma and low-grade nuclear cytology. Proliferation of spindle cells or foci of clear cells are also observed. Histochemically, the myxomatous stroma exhibits a positive reaction for alcian blue and colloidal iron stainings. Ultrastructurally, short microvilli are focally observed and junctional complexes are present. Recently, multiple losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15 and 22 in MTSCC have been elucidated by using comparative genomic hybridization. The prognosis of MTSCC is generally favorable, but some cases may show local recurrence or metastasis. Some cases with MTSCC seem to show overlapping histology with low-grade collecting-duct carcinoma. Therefore, further investigation will be needed to elucidate pathobiological characteristics of MTSCC.     

Review of metanephric adenoma of the kidney with focus on clinical and pathobiological aspects

The concept of metanephric adenoma has become established in recent years. Metanephric adenoma is a rare neoplasm. Macroscopically, the cut surface of the tumor displays a tan to gray or yellow color, and tumors generally form well-circumscribed masses. Histologically, tumors are composed of small epithelial cells that form small acini. Glomeruloid bodies, which are composed of lobulated papillary projections, are occasionally seen. Although there have been few studies using chromosomal analysis, two recent studies have shown partial monosomy or LOH of 2p. On the other hand, the concept of metanephric tumors has recently become broadened. These tumors include metanephric adenomas, adenofibromas and stromal tumors, and they compose a continuous histological spectrum. Therefore, further studies on various aspects are needed to identify the gene responsible for the occurrence of metanephric tumors and, furthermore, to clarify the association among the three types of metanephric tumors.     

Low-grade gliomas: clinical and pathobiological aspects

The optimal management of patients with low-grade gliomas remains a challenge for the treating physician. The natural history of the disease shows a large variety, and there is a substantial controversy about many of everyday treatment recommendations. However, new developments in clinical and basic research in neuro-oncology have occurred during the last years. In this review some of these new insights into clinical and biological aspects of low-grade gliomas are discussed, with focus on the translation of new knowledge from basic research into clinical practice. For example, molecular genetic profiling of tumour material has started to guide treatment recommendations and clinical management of some patients with oligodendrogliomas. Experimental studies of the different molecular pathways in tumour cells and in their normal counterparts involved in cell-cycle check-point control have elucidated some of the underlying mechanisms of resistance of gliomas to radiotherapy and chemotherapy. Finally, improved classification of the different subtypes of low-grade gliomas may be achieved in the near future by characterization of the genetic heterogeneity within the tumour and by identification of a putative stem cell as the origin of the tumour cells.     

Review of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions with focus on pathobiological aspect

The concept of Xp11.2 renal cell carcinoma (RCC) was recently established as a tumor affecting 15% of RCC patients <45 years. Many patients present with advanced stage with frequent lymph node metastases. Histologically, Xp11.2 RCC is characterized by mixed papillary nested/alveolar growth pattern and tumor cells with clear and/or eosinophilic, voluminous cytoplasm. Neoplastic cells show intense nuclear immunoreactivity to TFE3, while focal immunostaining for melanocytic markers, including melanosome-associated antigen or Melan A in some cases, are also noted. Alpha smooth muscle actin and TFEB are consistently negative. Ultrastructurally, the ASPL-TFE3 RCC variant contains rhomboid crystals in the cytoplasm, similar to that observed in alveolar soft part sarcoma. The fusion of the TFE3 gene with several different genes, including ASPL(17q25), PRCC(1q21), PSF(1q34), NonO (Xq12) and CLTC (17q23) have been identified to date. The behavior of Xp11.2 RCC in children and young adults is considered as indolent even when diagnosed at advanced stage, including lymph node metastasis. However, Xp11.2 RCC in older patients behaves in a more aggressive fashion. Therapy includes nephrectomy with extended lymphadenectomy. There may be a role for new protease inhibitors in advanced inoperable disease. Further research is required to correlate clinical behavior with the expanding genetic spectrum of this tumor, and to establish standard therapy protocols for primary and metastatic lesions.     

Renal collecting duct carcinoma. Report of a case with cytologic findings on fine needle aspiration

BACKGROUND: Collecting duct carcinoma (CDC) of the kidney is a rare type of renal cell carcinoma (RCC) of collecting duct origin. Cytologic differentiation of CDC from conventional RCC is important because CDC has a poorer prognosis than the latter. CASE: A 60-year-old male incidentally demonstrated a left renal mass that was hypovascular by angiography. Fine needle aspiration (FNA) revealed numerous clusters of cells arranged in a tubular structure. The cells consisted of highly atypical cells having large nuclei with coarse or vesicular chromatin, prominent nucleoli and lacy or granular cytoplasm. Based on these findings, which were indicative of high grade RCC, he underwent left radical nephrectomy and lymphadenectomy. Histologic and immunohistochemical findings, including anti-high-molecular-weight cytokeratin (HMCK) antibody, confirmed the diagnosis of CDC. CONCLUSION: CDC should be added to the differential diagnosis when the result of cytologic examination of a renal mass is suggestive of high grade RCC. These features of FNA smears, together with HMCK immunohistochemistry, can be useful for the cytologic differential diagnosis of renal tumors.     

Cancer specific mortality in patients with collecting duct vs. clear cell renal carcinoma

BackgroundCollecting duct carcinoma (CDC) is biologically more aggressive than clear cell renal cell carcinoma (ccRCC). We tested for differences in cancer specific mortality (CSM) rates according to CDC vs. ISUP (International Society of Urological Pathology) 4 ccRCC histological subtype. We hypothesized that the survival disadvantage still applies, even after most detailed adjustments.MethodsWithin Surveillance, Epidemiology, and End Results database (2004–2018), we identified 380 CDC vs. 6273 ISUP 4 ccRCC patients of all stages. Propensity score matching (age, sex, race/ethnicity, T, N, and M stages, nephrectomy, and systemic therapy status), Kaplan-Meier plots and multivariable Cox regression models were used.ResultsAll 380 CDC were matched (1:2) with 760 ISUP4 ccRCC patients. Prior to matching CDC patients exhibited higher rates of lymph node invasion (37.6 % vs. 14.7 %, p < 0.001), and of distant metastases (40.8 % vs. 30.4 %, p < 0.001). Systemic therapy rates were higher in CDC (29.5 % vs. 20.5 %, p < 0.001). However, nephrectomy rates were higher in ISUP4 ccRCC patients (97.5 % vs. 84.7 %, p < 0.001). After matching, in multivariable Cox regression models addressing CSM, CDC was associated with a HR of 1.5 (p < 0.001) in the overall population vs. 1.9 (p = 0.014) in stage I-II vs. 1.4 (p = 0.022) in stage III vs. 1.6 in stage IV (p < 0.001), relative to ISUP4 ccRCC.ConclusionCDC patients exhibited 40–90 % higher CSM than their ISUP4 ccRCC counterparts in the overall analysis, as well as in stage specific analyses. The CSM disadvantage applies despite higher rates of systemic therapy in CDC patients.     

Morphology of rabbit collecting duct.

Recently the assumed structural and functional homogeneity of the collecting duct (CD) has been questioned. The objective of this study was to determine if heterogeneity occurs in luminal surface membrane structure or in cytoplasmic configuration of cells in the collecting duct or both. Straight segments of cortical and medullary CD were examined in perfusion-fixed rabbit kidneys with scanning electron microscopy (SEM), light (LM) and transmission electron microscopy (TEM). Principal cells were the most abundant cells in all CD regions; intercalated cells comprised 37% of the cell population on the cortex, 18% in the outer medulla, and less than 1% in the inner medulla. SEM revealed two surface patterns among the ciliated principal cells: 1, located in the cortex and outer medulla, with few surface microvilli, and 2, located in the inner medulla, with abundant microvilli. Intercalated cells exhibited four distinctive luminal surface configurations: I, numerous short microvilli; II, both short and elongate microvilli; III, microplicae alone; and IV, both microvilli and microplicae. Intercalated cells with patterns I and II were predominant in the cortex, while cells with patterns III and IV were most common at the corticomedullary junction. TEM confirmed that marked variation existed in cytoplasmic structures of both principal and intercalated cells. These findings may either indicate the presence of several specific types of principal and intercalated cells or reflect different functional states of the principal and intercalated cells. Regardless of their significance, their presence must be considered in studies seeking to establish precise structural-functional relationships in this region of the rabbit renal tubule.     

Hepatocellular carcinoma: epidemiology and clinical aspects

Liver cancer is one of the most frequent solid cancers that kills more than 650,000 people around the world each year. Though great improvements have been done in last 10 years on the understanding the molecular mechanisms involved in liver oncogenesis, the prognosis of patients affected by liver cancer is still poor for most of them. Even in those where a relatively early diagnosis is done, the course of the disease is often fatal due to the underlying liver cirrhosis. In this review authors report the most recent findings on the pathogenesis of liver cancer and on therapeutic approaches, included those emerging from the most recent literature.     

Effects of increased perfusion pressure on medullary collecting duct function

The role of the medullary collecting duct in pressure natriuresis has not been established. In vivo microcatheterization was used to study the effect of an acute increase in blood pressure induced by bilateral carotid artery and vagal nerve ligation on medullary collecting duct function in anaesthetized rats. Increased fluid and electrolyte excretion during pressure natriuresis were accompanied by increased delivery of water, sodium, chloride, and potassium to the beginning of the medullary collecting duct, a change that was significantly greater than in a second series of time-control animals. These increases in delivery were within the range for which constant fractional NaCl reabsorption had been found previously. However, during increased perfusion pressure, reabsorption of both sodium and chloride in the medullary collecting duct as a fraction of delivered load were reduced from 81 +/- 4.1 to 51 +/- 9.3% (p less than 0.01) and from 65.7 +/- 6.0 to 42.7 +/- 9.1% (p less than 0.01), respectively. No significant changes in medullary collecting reabsorption were seen in the time controls. We conclude that increased perfusion pressure, in addition to increasing delivery to the medullary collecting duct, also inhibits sodium chloride reabsorption in this nephron segment.     

Pathophysiological aspects of cellular pyridine nucleotide metabolism: focus on the vascular endothelium. Review

In recent years, pyridine nucleotides NAD(H) and NADP(H) have been established as an important molecules in physiological and pathophysiological signaling and cell injury pathways. Protein modification is catalyzed by ADP-ribosyl transferases that attach the ADP-ribose moiety of NAD+ to specific aminoacid residues of the acceptor proteins, with significant changes in the function of these acceptors. Mono(ADP-ribosyl)ation reactions have been implicated to play a role both in physiological responses and in cellular responses to bacterial toxins. Cyclic ADP-ribose formation also utilizes NAD+ and primarily serves as physiological, signal transduction mechanisms regulating intracellular calcium homeostasis. In pathophysiological conditions associated with oxidative stress (such as various forms of inflammation and reperfusion injury), activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) occurs, with subsequent, substantial fall in cellular NAD+ and ATP levels, which can determine the viability and function of the affected cells. In addition, NADPH oxidases can significantly affect the balance and fate of NAD+ and NADP in oxidatively stressed cells and can facilitate the generation of various positive feedback cycles of injury. Under severe oxidant conditions, direct oxidative damage to NAD+ has also been reported. The current review focuses on PARP and on NADPH oxidases, as pathophysiologically relevant factors in creating disturbances in the cellular pyridine nucleotide balance. A separate section describes how these mechanisms apply to the pathogenesis of endothelial cell injury in selected cardiovascular pathophysiological conditions.     

Cartilage-specific autoimmunity in animal models and clinical aspects in patients - focus on relapsing polychondritis

Relapsing polychondritis is an autoimmune disease in which an inappropriate immune response destroys cartilage. Cartilage of the ears, larynx and nose rather than spine and joint cartilage is affected by a chronic relapsing and erosive inflammation. Several animal models for relapsing polychondritis have been published in which immunization with various cartilage proteins induces a variety of chondritis symptoms that mimic those seen in patients. In this review we describe the collagens, matrilin-1 and cartilage oligomeric matrix protein as potential autoantigens able to trigger the tissue-specific immune response seen both in patients and in animal models for relapsing polychondritis and related autoimmune diseases.     

Structural aspects of glycomes with a focus on N-glycosylation and glycoprotein folding

The pace of data accumulation in glycobiology has lately rapidly increased, largely due to high-throughput technologies. In this increasingly data-rich environment, computer science started to play a central role in handling the data, extracting significant biological information, and probing the missing parts of the 'scenery' by prediction, modelling or simulation. Investigating and comparing glycomes by bioinformatics and structural methods has great practical value and sharply increased in popularity in the past couple of years. In this context, advances have also been made with regard to structural aspects of protein N-glycosylation and consequences for glycoprotein folding. In these areas, however, an approach that integrates glycobiology with protein science is necessary.     

Flow regulation of collecting duct endothelin-1 production

Collecting duct (CD) endothelin-1 (ET-1) is an important autocrine inhibitor of CD Na(+) reabsorption. Salt loading is thought to increase CD ET-1 production; however, definitive evidence of this, as well as understanding of the mechanisms transducing this effect, is lacking. Tubule fluid flow increases in response to Na(+) loading; hence, we studied flow modulation of CD ET-1 production. Three days of a high-salt diet increased mouse and rat inner medullary CD (IMCD) ET-1 mRNA expression. Acute furosemide infusion increased urinary ET-1 excretion in anesthetized rats. Primary cultures of mouse or rat IMCD detached in response to flow using a closed perfusion chamber, consequently a CD cell line (mpkCCDcl4) was examined. Flow increased ET-1 mRNA at shear stress rates exceeding 1 dyne/cm(2), with the maximal effect seen between 2 and 10 dyne/cm(2). Induction of ET-1 mRNA was first evident after 1 h, and most apparent after 2 h, of flow. Inhibition of calmodulin or dihydropyridine-sensitive Ca(2+) channels did not alter the flow response; however, chelation of intracellular Ca(2+) or removal of extracellular Ca(2+) largely prevented flow-stimulated ET-1 mRNA accumulation. Downregulation of protein kinase C (PKC) using phorbol 12-myristate 13-acetate, or PKC inhibition with calphostin C, markedly reduced flow-stimulated ET-1 mRNA levels. Flow-stimulated ET-1 mRNA accumulation was abolished by inhibition of phospholipase C (PLC). Taken together, these data indicate that flow increases CD ET-1 production and this is dependent on extracellular and intracellular Ca(2+), PKC, and PLC. These studies suggest a novel pathway for coupling alterations in extracellular fluid volume to CD ET-1 production and ultimately control of CD Na(+) reabsorption.