Urothelial carcinoma of the upper urinary tract: inverted growth pattern is predictive of microsatellite instability

Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of hereditary nonpolyposis colorectal cancer syndrome (HNPCC), a disorder characterized by mutation or inactivation of a number of DNA mismatch repair genes and detectable as microsatellite instability (MSI). Some urothelial carcinomas display areas of endophytic, or inverted, growth. In this study, urothelial cancers of the upper urinary tract (n = 132) from patients treated at 2 tertiary care centers were studied to identify an association between growth pattern and MSI. Thirty-five neoplasms were microsatellite unstable (26.5%), and MSI was more frequent in papillary lesions than in sessile urothelial cancers (P = .033). The amount of inverted growth was estimated as a percentage of the total tumor. The interobserver and intraobserver concordance in recognizing inverted growth was good, and 65.7% of microsatellite-unstable tumors exhibited at least 20% of an inverted growth component, compared with only 17.5% of microsatellite-stable tumors (P < .0001). In this series, inverted growth predicted MSI with a sensitivity and specificity of .82. Inverted growth in urothelial carcinomas of the upper urinary tract may serve as a marker lesion for MSI and may help identify patients who should be offered testing for HNPCC.     

Hereditary nonpolyposis colorectal cancer syndrome in a patient with urothelial carcinoma of the upper urothelial tract

Urothelial carcinoma of the upper urinary tract is relatively uncommon but may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability or loss of the respective protein by immunostaining. No well-established screening test is available for urothelial carcinomas of the upper urinary tract, and little is known of the clinical impact of screening for HNPCC in patients with upper urinary tract cancer. We describe herein a patient with a urothelial carcinoma of the ureter and a strongly positive history of cancer, who was subsequently found to have HNPCC. Our findings reinforce the importance of obtaining a comprehensive history of cancer in patients with urothelial carcinoma of the renal pelvis and ureter. Subsequent identification of individuals with HNPCC enables the patient and at-risk relatives to benefit from targeted surveillance and management programs.     

Histologic features distinguish microsatellite-high from microsatellite-low and microsatellite-stable colorectal carcinomas, but do not differentiate germline mutations from methylation of the MLH1 promoter

The detection of microsatellite-unstable (microsatellite instability [MSI]) colorectal carcinomas (CRCs) has prognostic value and can help screen for Lynch syndrome. We determined which histologic features are associated with MSI status and presence of germline mutation and/or methylation of MLH1 promoter. Patients diagnosed with CRC were offered participation in the Columbus-area hereditary nonpolyposis colorectal cancer syndrome study regardless of age or family history. Tumors were evaluated for MSI using a modified Bethesda panel of microsatellite markers. Methylation status of the MLH1 promoter was evaluated by methylation-specific polymerase chain reaction and bisulfite PCR followed by restriction digestion of tumor DNA. All patients with microsatellite-unstable tumors underwent mutation analysis of the MLH1, MSH2, and MSH6 genes by full sequencing of genomic DNA and by multiplex ligation probe assay of MLH1 and MSH2. Histologic end points were tumor type, grade, percentage of mucin, border, and lymphoid host response. Of the 482 CRCs, 87 were MSI with 69 MSI high (MSI-H), 18 MSI low (MSI-L), and 395 microsatellite stable (MSS). Of 87 MSI tumors, 12 had germline mutations and 34 had methylation of the MLH1 promoter. Younger age, but not histologic features, was significantly associated with a germline mutation. Percentage of mucin, histologic type, grade, and lymphoid host response differed significantly between MSI-H when compared with MSI-L or MSS. No difference was found between MSI-L versus MSS. Histologic features are associated with MSI-H CRC and are helpful to differentiate MSI-H from MSI-L and MSS. These features are not useful to distinguish MSI-L from MSS carcinomas, and those with a deleterious germline hereditary nonpolyposis colorectal cancer syndrome mutation from those with methylation of the MLH1 promoter region.     

Microsatellite Instability and Mutation of DNA Mismatch Repair Genes in Gliomas

Microsatellite instability (MSI) has been identified in various human cancers, particularly those associated with the hereditary nonpolyposis colorectal cancer syndrome. Although gliomas have been reported in a few hereditary nonpolyposis colorectal cancer syndrome kindred, data on the incidence of MSI in gliomas are conflicting, and the nature of the mismatch repair (MMR) defect is not known. We established the incidence of MSI and the underlying MMR gene mutation in 22 patients ages 45 years or less with sporadic high-grade gliomas (17 glioblastomas, 3 anaplastic astrocytomas, and 2 mixed gliomas, grade III). Using five microsatellite loci, four patients (18%) had high level MSI, with at least 40% unstable loci. Germline MMR gene mutation was detected in all four patients, with inactivation of the second allele of the corresponding MMR gene or loss of protein expression in the tumor tissue. Frameshift mutation in the mononucleotide tract of insulin-like growth factor type II receptor was found in one high-level MSI glioma, but none was found in the transforming growth factor β type II receptor and the Bax genes. There was no family history of cancer in three of the patients, and although one patient did have a family history of colorectal carcinoma, the case did not satisfy the Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome. Three patients developed metachronous colorectal adenocarcinomas, fitting the criteria of Turcot’s syndrome. Thus, MSI and germline MMR gene mutation is present in a subset of young glioma patients, and these patients and their family members are at risk of developing other hereditary nonpolyposis colorectal cancer syndrome-related tumors, in particular colorectal carcinomas. These results have important implications in the genetic testing and management of young patients with glioma and their families.     

Unusual tumors associated with the hereditary nonpolyposis colorectal cancer syndrome.

The molecular pathogenesis of tumors outside the usual tumor spectrum for hereditary nonpolyposis colorectal cancer (HNPCC) is currently controversial. Specifically, it is not known whether these tumors are related to defects in DNA mismatch repair or arise independently of this defect in these patients. Here, we report two young patients, each with a known MSH2 mutation in the family, who developed rare tumors (adrenal cortical carcinoma and anaplastic carcinoma of the thyroid) that are not usually associated with HNPCC. Both of these patients were members of families that fulfilled modified Amsterdam (Amsterdam II) criteria for this familial cancer syndrome. Both the adrenal tumor and the thyroid tumor showed complete loss of immunohistochemical expression for MSH2 protein. Neither tumor was considered microsatellite instability-high following microsatellite instability analysis using the established National Cancer Institute panel of five microsatellite markers. To our knowledge, MSH2 defects in these types of tumors have not been previously reported in patients with the HNPCC syndrome. Our results suggest that microsatellite instability analysis using the National Cancer Institute panel of five microsatellite markers may not detect microsatellite instability in tumors that fall outside the usual tumor spectrum of this syndrome. Therefore, when analyzing unusual tumors in patients with known or suspected HNPCC syndrome, we advocate the performance of immunohistochemistry for mismatch repair gene products in addition to microsatellite instability analysis.     

Spectrum of molecular alterations in colorectal, upper urinary tract, endocervical, and renal carcinomas arising in a patient with hereditary non-polyposis colorectal cancer

Hereditary nonpolyposis colon cancer (HNPCC) syndrome is the most frequent hereditary cancer syndrome predisposing to cancers of various locations, especially colon, endometrium, stomach, and upper urinary tract. Carcinomas of the kidney parenchyma are not considered as an HNPCC-related tumor. HNPCC tumors are characterized by microsatellite instability (MSI) due to a defect in mismatch repair (MMR) and carry somatic frameshift mutations in mononucleotide repeats within the coding regions of key genes. We report the first case of a papillary carcinoma of the kidney in an HNPCC patient who developed carcinomas of the upper urinary tract, endocervix, and colon. Whereas the HNPCC-related tumors demonstrated MSI phenotype, loss of MSH2 protein expression, and frameshift mutations in several of the 13 target genes analyzed, the kidney cancer displayed MSS phenotype, normal MMR protein expression, and no frameshift mutation in target genes. Our observations do not support the possibility that papillary carcinomas are part of HNPCC syndrome.     

Hereditary nonpolyposis colorectal cancer identification and surveillance of high-risk families

Hereditary nonpolyposis colorectal cancer is an autosomal dominant condition caused by highly penetrant gene mutations. It is characterized by increased susceptibility for a specific group of cancer, mainly colorectal cancer. The syndrome originates from the inheritance of mutations in DNA mismatch repair genes. The most commonly affected genes in hereditary nonpolyposis colorectal cancer are hMLH1 and hMSH2. Their deficient expression renders the cell susceptible to the accumulation of many molecular defects, a condition which can be evaluated by the instability in sections of base repeats in the genoma known as microsatellite instability. The molecular detection of hereditary nonpolyposis colorectal cancer is possible in most of the highly suspicious cases. Genetic tests for hereditary nonpolyposis colorectal cancer also allow characterization of the individual that bears the mutation within a family. The high cost and restricted availability of these tests hamper their use for every person presenting colorectal cancer. Due to this fact, some clinical criteria have been developed by a hereditary nonpolyposis colorectal cancer international organization to select families with a high probability of carrying the mutation. Once families at risk are identified, they are encouraged to join a screening program that aims at early detection of hereditary nonpolyposis colorectal cancer-related cancers, increasing the possibility of its prevention and early detection.     

Microsatellite instability is a rare finding in tumors of patients with both primary renal and rectal neoplasms

Multiple primary malignancies in an individual patient are thought to be a common feature of hereditary disease. Asymptomatic renal neoplasms have been described in up to 4% of rectal cancer patients. We have assessed whether microsatellite instability is present in the rectal and renal tumors of patients presenting at our institution with primary renal and rectal cancers. Of the seven patients presenting with both diagnoses, paraffin blocks were available from five cases of colorectal cancer and six renal neoplasms. Five of six cases of renal tumors were informative and all were microsatellite instability (MSI) stable. One renal tumor was deemed inconclusive because of inadequate amplification. Four of five cases of rectal cancer were MSI stable. These data suggest that these renal and rectal tumors developed independently of a mismatch repair defect and that, unlike epithelial tumors of the renal collecting system, renal parenchymal lesions are unlikely to be part of the spectrum of hereditary nonpolyposis colorectal cancer.     

Microsatellite instability as a predictor of a mutation in a DNA mismatch repair gene in familial colorectal cancer

Germline alterations in human DNA mismatch repair genes are associated with hereditary nonpolyposis colorectal cancer (HNPCC). Mutation analysis of the genes reveals carriers with a high risk of colorectal cancer, who will benefit from surveillance. We wanted to find the best predictive parameter of a germline mutation in those genes among patients with familial colorectal cancer. Affected members from a total of 83 unrelated colorectal cancer families previously analyzed for mutations in MSH2 and MLH1 were used to evaluate different parameters' ability to predict a germline mutation. We studied various clinical criteria such as family structure, age of onset, and prevalence of endometrial cancer, as well as microsatellite instability in the tumors from the families. In total, 124 tumors from 59 of the families were tested for microsatellite instability (MSI) using PCR-based mono- and dinucleotide markers to establish whether the families could be scored as MSI-positive or -negative. The finding of MSI-positive tumors in a family was the best predictor of a germline mutation, and was found in 73% of the MSI-positive, but in less than 3% of the MSI-negative families (P < 0.0001). In contrast, MSI in unselected colorectal cancer is not as useful, since most of these MSI-positive tumors are sporadic. The finding of microsatellite instability in colorectal tumors seems efficient enough even to select those with germline mutations among families fulfilling HNPCC Amsterdam criteria, once used in identification of the DNA mismatch repair genes. Genes Chromosomes Cancer 27:17-25, 2000.     

Characterization of mutator pathway in younger-age-onset colorectal adenocarcinomas

The high-frequency microsatellite instability (MSI-H) phenotype, frequently identified in hereditary nonpolyposis colorectal cancer (HNPCC), also accounts for approximately 15% of sporadic colorectal cancers. Microsatellite instability (MSI) occurs from the mutational inactivation of the DNA mismatch repair genes, i.e. hMSH2 and hMLH1 in HNPCC, as well as from epigenetic inactivation of hMLH1 in sporadic colorectal tumors. The mutator pathway including microsatellite instability, hMLH1 promoter methylation, and hMSH2 and hMLH1 mutation patterns were identified in 21 sporadic colorectal adenocarcinoma patients younger than 30 yr excluding HNPCC. More than half of tumors showed MSI, with five MSI-H and six MSI-L (low-frequency microsatellite instability). Three of six MSI-H tumors showed the hMLH1 promoter methylation and did not express the hMLH1 protein. On the other hand, all MSI-L and all MSS (microsatellite stable) tumors expressed both hMSH2 and hMLH1 proteins. Two novel mutations, i.e. a missense mutation in hMLH1 and a splice-site alteration in hMSH2, were identified in two patients respectively. Although mutator pathway was implicated in younger-age-onset colorectal carcinogenesis, many tumors appeared to evolve from different genetic events other than hMSH2 and hMLH1 mutations frequently identified in HNPCC.     

Microsatellite-unstable mucinous colorectal carcinoma occurring in the elderly: comparison with medullary type poorly differentiated adenocarcinoma

Mucinous carcinoma and poorly differentiated adenocarcinoma of the large intestine have a high frequency of microsatellite instability, and their occurrence increases gradually with age. To elucidate the clinicopathological and immunohistochemical features of microsatellite-unstable mucinous carcinoma and compare the tumor with medullary type poorly differentiated adenocarcinoma, the clinicopathological status and expression of mucin core and hMLH1 proteins were studied in 15 microsatellite-unstable and 20 microsatellite-stable mucinous colorectal carcinomas occurring in elderly patients, and compared with 23 cases of medullary type poorly differentiated adenocarcinoma in which 21 cases were microsatellite-unstable. Thirteen (87%) of 15 microsatellite-unstable carcinomas exhibited absent hMLH1 expression compared with three (15%) of 20 microsatellite-stable carcinomas (P < 0.01). The proportion (87%) of positive MUC5AC expression in microsatellite-unstable mucinous carcinoma was significantly higher than that (45%) in microsatellite-stable mucinous carcinoma (P = 0.01). Compared with microsatellite-stable mucinous carcinoma, microsatellite-unstable mucinous carcinomas were significantly associated with a proximal location, intra- and peritumoral inflammatory cell infiltration, frequent MUC5AC expression, a low incidence of lymph node metastasis and absent hMLH1 protein expression, which is not different to medullary type poorly differentiated adenocarcinoma except for MUC2 expression and age-related occurrence. These results suggest that microsatellite-unstable mucinous carcinoma occurring in the elderly shares clinicopathological and molecular features with medullary type poorly differentiated adenocarcinoma and that microsatellite instability with absent hMLH1 expression plays an important role in the development of these two carcinomas.     

Identification and management of HNPCC syndrome (hereditary non polyposis colon cancer), hereditary predisposition to colorectal and endometrial adenocarcinomas

BACKGROUND: The HNPCC syndrome (hereditary nonpolyposis colon cancer) is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for small intestine, urothelial, ovary, stomach and biliary tract carcinomas. HNPCC syndrome is responsible for 5% of colorectal cancers. Identification and management of this disease are part of a multidisciplinary procedure. METHODS: Twelve experts have been mandated by the French Health Ministry to analyze and synthesize their consensus position, and the resulting document has been reviewed by an additional group of 4 independent experts. MAIN RECOMMENDATIONS: The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a 2-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks, but other organs being at low lifetime risk, no specific surveillance will be proposed.     

A cost-effective algorithm for hereditary nonpolyposis colorectal cancer detection

Colorectal cancer with microsatellite instability (MSI) may occur sporadically or be inherited in cases of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. However, there is no consensus as to which patients must be tested and how to test MSI. In this study, MSI was tested by immunohistochemical analysis and by polymerase chain reaction in 148 cases of colorectal cancer, and methylation of the hMLH1 promoter was examined. MSI status was correlated with tumor phenotype. We found that localization, tumor infiltrating lymphocytes, and mucinous differentiation were predictive of high-frequency MSI (MSI-H) colorectal cancer and might be used to select cases for MSI analysis. Immunohistochemical analysis detected most MSI-H colorectal cancer and might constitute the first step in MSI detection. Absence of hMLH1 promoter methylation in MSI-H colorectal cancer could be predictive of hereditary colorectal cancer, and, hence, methylation analysis might constitute the second step in the identification of patients with HNPCC.     

Microsatellite instability is infrequent in medullary breast cancer

Microsatellite instability (MSI), characterized by contraction or expansion in microsatellite length or short tandem repeats compared with germline lengths, is found in 85% to 90% of colon cancer arising in hereditary nonpolyposis colorectal cancer families. These cancers commonly have characteristic histologic appearances, including medullary features with intense lymphoid infiltrates. In pancreatic cancer, a rare medullary histologic subtype more often demonstrates MSI than the more common adenocarcinoma subtype. We hypothesized that the medullary histologic pattern might correlate with MSI in additional tumor types and analyzed 8 cases of typical and atypical medullary carcinoma of the breast. Tumor and normal DNA was extracted from paraffinized tissue blocks of tumor and histologically uninvolved axillary lymph nodes, respectively. We analyzed the tumors for instability in 5 primary (BAT25, BAT26, D17S250, D5S346, D2S123) and 3 alternative (BAT40, D18S55, D18S58) microsatellites recommended at the National Cancer Institute--sponsored conference for diagnosis of MSI in colorectal cancer. All 8 tumors were microsatellite stable at the 8 loci, suggesting that MSI is not commonly associated with medullary or atypical medullary breast carcinoma, in contrast with the reported association with medullary tumors of the colon and pancreas.     

Microsatellite Instability and hMLH1 and hMSH2 expression analysis in familial and sporadic colorectal cancer

Immunohistochemical expression analysis of mismatch repair gene products has been suggested for the prediction of hereditary nonpolyposis colorectal cancer (HNPCC) carrier status in cancer families and the selection of microsatellite instability (MSI)-positive tumors in sporadic colorectal cancer. In this study, we aimed to evaluate hMSH2 and hMLH1 immunohistochemistry in familial and sporadic colorectal cancer. We found that immunohistochemistry allowed us to identify patients with germline mutations in hMSH2 and many cases with germline mutations in hMLH1. However, some missense and truncating mutations may be missed. In addition, hMLH1 promoter methylation, commonly occurring in familial and sporadic MSI-positive colorectal cancer, can complicate the interpretation of immunohistochemical expression analyses. Our results suggest that immunohistochemistry cannot replace testing for MSI to predict HNPCC carrier status or identify MSI-positive sporadic colorectal cancer.     

Clinical and pathological significance of microsatellite instability in sporadic endometrial carcinoma.

Defective DNA mismatch repair in neoplasia is manifested by extra, aberrant bands within multiple microsatellite markers. The replication error (RER) phenotype is present in most colorectal and endometrial carcinomas in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. In addition, a minority of sporadic colorectal and endometrial carcinomas are RER positive. RER in sporadic colorectal carcinomas has been associated with improved prognosis, but its clinical significance in sporadic endometrial cancer has not been characterized. We analyzed DNA extracted from 109 formalin-fixed sporadic endometrial carcinomas for microsatellite instability. The RER-positive phenotype was demonstrated by microsatellite instability in more than one of the eight dinucleotide markers tested. RER was correlated with pathological and clinical parameters as well as with immunohistochemical staining for the p53 gene product and alterations in codon 12 of Ki-ras. Nine percent of the endometrial carcinomas were RER positive, and RER was significantly associated with high grade and adverse outcome. We found no significant correlation of RER with histological subtype, stage, depth of invasion, mutations in the 12th codon of Ki-ras, or p53 immunoreactivity. We conclude that the RER phenotype is present in a minority of sporadic endometrial carcinomas and is associated with high grade and poor prognosis.     

Frameshift mutations of human gastrin receptor gene (hGARE) in gastrointestinal cancers with microsatellite instability

Gastrointestinal tumors with DNA mismatch repair (MMR) defects show microsatellite instability (MSI) and harbor frameshift mutations in coding mononucleotide repeats of cancer-related genes (targets). We assessed MSI status in 233 sporadic gastrointestinal tumors. We classified as MSI-H (high-frequency microsatellite instability) 15 (10%) of 150 colorectal cancers and 13 (16%) of 83 gastric cancers. We searched for frameshift mutations in a coding poly(T)(8) tract within the gastrin receptor gene (hGARE), which has a potential role in gastrointestinal carcinogenesis. To this purpose, we screened 43 unstable tumors (including 15 hereditary nonpolyposis colorectal cancer cases previously classified as MSI-H), 98 stable tumors, as well as 3 MMR-deficient and 4 MMR-proficient gastrointestinal cancer cell lines. We found mutations in 8 (19%) of the 43 MSI-H tumors but in none of the 98 stable cancers. hGARE mutation frequency was similar in gastric (23%) and colorectal cancers, including sporadic (13%) and hereditary (20%) cases. All mutated tumors proved to harbor frameshift mutations in other cancer-related genes that are considered as targets in MSI tumorigenesis. The MMR-deficient and gastrin-sensitive LoVo colorectal cancer cells also showed a hGARE heterozygous frameshift mutation, but expressed only the mutated allele. All detected mutations can be predicted to generate a truncated protein carrying amino acid changes. On the basis of genetic findings, we propose hGARE as a new candidate target gene in MSI tumorigenesis. Functional studies are warranted to elucidate the mechanism by which the hGARE mutation might contribute to gastrointestinal carcinogenesis.     

Correlation between in vitro tetraploidy in skin fibroblasts and development of sporadic colorectal carcinomas

In vitro tetraploidy (IVT) in skin fibroblasts cultures measured by flow cytometry was compared with histological type and degree of dysplasia in 22 patients with adenomas of the colon and rectum. Furthermore, IVT was compared with stage and differentiation in 36 patients with carcinoma of the colon and rectum. In vitro tetraploidy in skin fibroblasts was correlated to type as well as dysplasia in adenomas and differentiation in carcinomas but was not correlated to Dukes' stage in carcinomas. Skin fibroblast genetic instability, expressed as increased IVT (IVT+), has been reported to reflect a genetic predisposition to colorectal cancer in the hereditary nonpolyposis colorectal cancer syndrome. Because IVT+, which appears to be associated with the progression of adenomas to carcinomas, also is found in many of the non-syndrome colorectal cancers, we suggest that development of colorectal cancer is considerably influenced by the constitutive genetic instability of the autosomal dominant colorectal cancer syndromes.     

Neoplasms of the upper urinary tract: a review with focus on urothelial carcinoma of the pelvicalyceal system and aspects related to its diagnosis and reporting

Tumors of the renal pelvis account for approximately 7% to 8% of all renal malignancies, greater than 90% of these are of urothelial (transitional cell) origin. These tumors more typically occur in the sixth to eight decade with a slight male preponderance. Varying risk factors for urothelial carcinomas of the upper tract are recognized including environmental and occupational hazards, chemotherapeutic exposure, and previous history of urinary bladder or ureteral carcinomas. Tumor multifocality is frequent and additional tumors may arise in the ureter, bladder, or on the contralateral side. The histopathologic nuances presented by urothelial carcinoma in this region are generally similar to those in the urinary bladder. Though the World Health Organization 2004/International Society of Urological Pathology system used in the bladder is customarily also employed for grading of urothelial tumors of this region, its prognostic significance at this site is not entirely clear as most tumors are treated with nephroureterectomy irrespective of the grade of the tumor. Histologic grade may be an independent prognostic factor in papillary pT1 tumors; however, most pT2 and higher stage tumors tend to be nonpapillary and of higher grade. Despite advances in treatment modalities with sophisticated endoscopic techniques, tumor stage remains the most important prognostic factor. There are several confounding issues related to staging such as the variable presence and thickness of subepithelial connective tissue and muscularis in the renal calyces, renal pelvis, and the ureter; intratubular pagetoid cancer spread (pTis vs. pT3); and assessing invasion in papillary neoplasms with endophytic or inverted growth. Careful gross examination with adequate sampling and understanding the microanatomy of the pelvicalyceal wall are crucial for accurate stage assignment. Poor fixation of large friable tumors and processing artifacts may compound difficulties in accurate staging. This review focuses on urothelial carcinoma of the upper tract highlighting issues related to its diagnosis, staging, and reporting.     

Squamous cell carcinoma in a duplicated renal pelvis

We report an extremely rare case of squamous cell carcinoma (SCC) of the renal pelvis associated with an incompletely duplicated renal pelvis and ureter. A 71-year-old woman presented with left lower back pain and gross hematuria. Urinary cytology showed atypical squamous cells. Computed tomography, magnetic resonance imaging and retrograde pyelography revealed left incompletely duplicated renal pelvis and ureter and a mass in the left upper renal pelvis. A clinical diagnosis of left renal pelvic cancer was made and the patient underwent total nephroureterectomy. Histological examination of the resected specimen revealed SCC with marked keratinization in the upper renal pelvis. The tumor had invaded the renal parenchyma and perinephric fat. There was no urothelial carcinoma component. The pathological stage was pT4 N0. There was no evidence of recurrence 6 months postoperatively. Because the prognosis of SCC of the upper urinary tract is poor, urologists and pathologists should be aware that SCC may develop in duplicated urinary systems.