Mild hypophosphatasia may be twice as prevalent as previously estimated: an effective clinical algorithm to detect undiagnosed cases.

OBJECTIVES: Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented. METHODS: Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario Clínico San Cecilio in the period June 2018 - December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal-5'-phosphate (PLP) and genetic study of ALPL gene. RESULTS: Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∼40 %). CONCLUSIONS: This new algorithm was effective in detecting previously undiagnosed cases of HPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder.

References Values of Soluble α-Klotho Serum Levels Using an Enzyme-Linked Immunosorbent Assay in Healthy Adults Aged 18-85 Years.

α-Klotho protein is a powerful predictor of the aging process and lifespan. Although lowered circulating soluble α-Klotho levels have been observed in aged non-healthy individuals, no specific reference values across a wide range of ages and sex using an enzyme-linked immunosorbent assay (ELISA) are available for larger cohorts of healthy individuals. The present analytical cross-sectional study was aimed to establish the reference values of soluble α-Klotho serum levels in healthy adults by age and sex groups. A total of 346 (59% women) healthy individuals aged from 18 to 85 years were recruited. Subjects were divided by sex and age as: (i) young (18−34.9 years), (ii) middle-aged (35−54.9 years), and (iii) senior (55−85 years) individuals. The soluble α-Klotho levels were measured in serum using ELISA. Senior adults were the age-group that presented the lowest soluble α-Klotho serum levels (p < 0.01), with age showing a negative association with soluble α-Klotho serum levels (p < 0.001). No differences between sexes were observed. Therefore, soluble α-Klotho levels were especially decreased­regardless of sex­in our cohort of healthy individuals because of the physiological decline derived from the aging process. We recommend routine assessments of soluble α-Klotho levels using ELISA as a simple and cheap detectable marker of aging that improves quality of life in the elderly.

Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective.

The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted (BRCA1/2) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at BRCA2 (47/98), BRCA1 (24/98), PALB2 (8/51), ATM (7/51), CHEK2 (6/51) MSH6, (2/51), RAD51C (2/51) and TP53 (2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for BRCA1 and MSH6 pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for BRCA2 and BRCA1 pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures (p = 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from BRCA1 and BRCA2, and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for BRCA1/2 between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.

Hypophosphatasia: A Unique Disorder of Bone Mineralization.

Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5'-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.

HLC Pair Suppression as a Risk Factor for Bacterial Bloodstream Infections and Early Mortality in Newly Diagnosed Intact Immunoglobulin Multiple Myeloma Patients.

Despite the outstanding progresses in Multiple Myeloma treatment options in the last decades, it remains an incurable disease nowadays. Infectious events are a complication due to an impaired immune system associated with MM, sometimes a life-threatening one, particularly on the first months after the diagnosis. Both the underlying disease and treatment can contribute to the infection risk, so a biomarker that assess this risk could be highly relevant for a more tailored management of the patient. The measurement of the heavy+light chain (HLC) pairs of immunoglobulins in serum allows the quantification of both the monoclonal component and the non-monoclonal immunoglobulin of the same isotype. This approach has demonstrated high sensitivity for the detection of the clonality and prognostic value for MM. HLC pair suppression itself has prognostic power and it has been proposed to be a reflection of the immune system' attempt to control the tumor. In this study we evaluated the impact of the HLC pair suppression on the rate of bloodstream infections (BSI) and early death in 115 newly diagnosed MM patients. Twenty-one percent of the patients suffered a BSI in the first 6 months after diagnosis, of which 58% died within this period, accounting to 67% of the early deaths in global and highlighting the major impact of infections on MM patients in a "real world" setting. Severe HLC pair suppression identified patients with a higher risk of early BSI (HR: 6,97, p=0,009), and extreme HLC pair suppression together with BSI event and age >65 were independent risk factors for early death (p<0,001). Based on these factors, a stratification model was generated to allow identify patients at a higher risk of early death and poorer OS, with an apparently better performance than the ISS on the early death context. In conclusion, HLC pair suppression associates with both a higher risk of life-threatening early infection and early death in newly diagnosed MM patients. Patients older than 65 with extreme HLC pair suppression and BSI are at a high risk of early death, and thus patients presenting with these criteria have a very adverse prognosis.

The value of hypercalciuria in patients with osteopenia versus osteoporosis.

The aim of this study was to analyze the presence of lithogenic metabolic factors in the blood and urine of patients with osteopenia versus osteoporosis. This is a cross-sectional study including 67 patients who were divided into two groups according to the presence of either osteopenia or osteoporosis as measured by bone densitometry: group 1-40 patients with osteopenia (22 men and 18 women) and group 2-27 patients with osteoporosis (13 men and 14 women). Metabolic studies were performed on the blood and urine; statistical analysis was performed comparing means and conducting linear correlation and multivariate analyses with SPSS. Statistical significance was considered to be p ≤ 0.05. The mean age of patients in group 1 was 52.9 ± 12.8 years versus 50.3 ± 11.4 in group 2; the difference was not statistically significant. In group 2, higher levels of osteocalcin, ß-crosslaps, urinary calcium, fasting urine calcium/creatinine, 24 h urine calcium/creatinine and 24 h oxaluria were observed compared to group 1. In the multivariate analysis, only the ß-crosslaps and urinary calcium were independently associated with osteoporosis. It would be advisable to determine the urinary calcium levels in patients with osteoporosis since altered levels may necessitate modifying the diagnostic and therapeutic approach to osteoporosis.

Bone remodeling markers as lithogenic risk factors in patients with osteopenia-osteoporosis.

PURPOSE: To analyze the presence of phosphocalcic metabolism disorders in patients with osteopenia-osteoporosis without nephrolithiasis with respect to a control group. METHODS: A cross-sectional study was conducted in patients with osteopenia-osteoporosis without nephrolithiasis (n = 67) in lumbar spine or femur and in a control group (n = 61) with no lithiasis or bone disorders. Blood bone markers, phosphocalcic metabolism, fasting urine, 24-h urine lithogenic risk factors, and densitometry were recorded in both groups. SPSS 20.0 was used for statistical analysis. RESULTS: In comparison with the controls, significantly higher blood calcium (9.27 ± 0.36 vs. 9.57 ± 0.38, p = 0.0001), intact parathormone (45.6 ± 14.9 vs. 53.8 ± 18.9, p = 0.008), and alkaline phosphatase (61.9 ± 20.9 vs. 70.74 ± 18.9, p = 0.014) levels were found in patients with osteopenia-osteoporosis. In the 24-h urine test, citrate (1010.7 ± 647.8 vs. 617.6 ± 315.8, p = 0.0001) and oxalate (28.21 ± 17.65 vs. 22.11 ± 16.49, p = 0.045) levels were significantly lower in osteopenia-osteoporosis patients than in controls, with no significant difference in calcium (187.3 ± 106.9 vs. 207.06 ± 98.12, p = 0.27) or uric acid (540.7 ± 186.2 vs. 511.9 ± 167.06, p = 0.35) levels. Patients with osteopenia-osteoporosis had significantly higher levels of lithogenic risk factors associated with bone remodeling, including significantly increased ß-crosslaps and osteocalcin values and higher ß-crosslaps/osteocalcin ratios. CONCLUSION: Patients with osteopenia-osteoporosis without nephrolithiasis showed phosphocalcic metabolism disorders as well as lower urinary citrate and higher ß-crosslaps/osteocalcin and fasting calcium/creatinine ratios, which would increase the risk of nephrolithiasis. Hence, prospective studies are warranted to evaluate the long-term risks.

Analysis of vitamin D deficiency in calcium stone-forming patients.

PURPOSE: The aim of this study is to analyse the percentage of hypovitaminosis D, as well as its relationship with the various parameters of calcium-phosphate metabolism. METHODS: A case control study was conducted on 366 patients, divided into two groups: Group 1: 127 non-stone-forming patients, and Group 2: 239 calcium stone forming. A study was performed on calcium-phosphate metabolism and urinary lithogenic factors. The percentage of vitamin D deficiency (25-OH-vitamin D levels <20 ng/ml) between the groups was analysed and compared. The SPSS 20.0 statistics program was used for the analysis, with a p ≤ .05 being considered significant. RESULTS: The mean age of Group 1 was 52.1 years compared to 49.6 years in Group 2, with no significant differences (p = .07). Vitamin D levels were lower in Group 2 compared to Group 1 (25.7 vs. 28.4 ng/ml, p = .02). A vitamin D deficiency was observed in 28 % of the Group 2 stone-forming patients versus 15.7 % in Group 1 (p = .009), with an odds ratio (OR) of 2.09 (95 % CI; 1.19-3.63). In the stone-forming patients with a vitamin D deficiency, the only difference observed was the higher levels of iPTH compared to those stone-formers with a normal vitamin D (56.9 vs. 45.5 pg/ml, respectively; p = .0001). CONCLUSION: Calcium stone-forming patients have lower mean levels of vitamin D and a higher percentage of hypovitaminosis D than in non-stone-forming patients. This was only related to increased iPTH levels, with urine calcium and other lithogenic parameters having no obvious effect.

Urine Calcium and Bone Mineral Density in Calcium Stone-Forming Patients Treated with Alendronate and Hydrochlorothiazide.

INTRODUCTION: The objective was to evaluate the effect of hydrochlorothiazide and alendronate on urine calcium and bone mineral density in calcium stone-forming patients. MATERIAL AND METHODS: A prospective, non-randomized, non-observational comparative study was performed; this study included 111 patients with recurrent calcium stones, divided into 3 groups according to the treatment received. Group 1: 36 patients were treated with alendronate, 70 mg/week; Group 2: 34 patients were treated with alendronate, 70 mg/week + hydrochlorothiazide, 50 mg/day; Group 3: 41 patients were treated with hydrochlorothiazide, 50 mg/day. All patients received recommendations on diet and fluid intake. Other variables of bone mineral density were studied and analyzed, including bone remodeling markers and urinary calcium before and after 2 years of treatment. The statistical analysis was performed using the SPSS 17.0 program, with a statistical significance of p < 0.05. RESULTS: After 2 years of treatment, a significant difference was observed in the ß-crosslaps and a bone mineral density improvement in Group 1, along with a decrease in urinary calcium. In Group 3, a statistically significant difference was found in urinary calcium and fasting calcium/creatinine ratio, as well as an improvement in bone mineral density after 2 years of medical treatment. In Group 2 patients treated with the combination, there was an improvement in bone mineral density and a decrease in the ß-crosslaps marker similar to patients in Group 1, and a decrease in urinary calcium similar to those in Group 3. CONCLUSION: Combined alendronate + hydrochlorothiazide treatment offers the best results along with the improvement in bone mineral density and decrease in urine calcium in patients with recurrent calcium stones.

The importance of calciuria as lithogenic factors in patients with osteopenia/osteoporosis.

PURPOSE: Recurrent kidney stones are associated with bone mineral density loss, altered bone remodeling markers, hypercalciuria and increased in fasting calcium/creatinine ratio. The objective was to determine biochemical alterations in urine in patients with osteopenia/osteoporosis without calcium kidney stones compared with patients with calcium kidney stones. METHODS: This is a cross-sectional study including 142 patients who were divided in two groups: Group 1 (patients with recurrent calcium kidney stones) and Group 2 (patients with osteopenia/osteoporosis in the lumbar spine or hip). Analyses of bone mineral density, calcium-phosphorous and bone metabolism and lithogenic risk factors in fasting urine samples and 24-h urine samples were performed. Statistical analysis was carried out with SPSS 17.0. A p ≤ 0.05 was considered statistically significant. RESULTS: Patients in Group 2 presented greater loss of bone mineral density and more elevated alkaline phosphatase, iPTH, phosphorous and ß-crosslaps levels, as compared to patients in Group 1. However, Group 1 presented greater urine calcium, oxalate and uric acid and a higher proportion of hypocitraturia, hypercalciuria and hyperoxaluria, as compared to Group 2. Multivariate analysis revealed that advanced age and ß-crosslaps levels are risk factors for bone mineral density loss, while low urinary calcium excretion was protective against bone demineralization. CONCLUSION: Patients with osteopenia/osteoporosis without lithiasis present some urinary biochemical alterations. This would explain the lack of lithogenic activity, although low calcium excretion in 24-h urine samples is a protective factor against the loss of bone mineral density.

Quantitative-fluorescent-PCR versus full karyotyping in prenatal diagnosis of common chromosome aneuploidies in southern Spain.

BACKGROUND: Quantitative-fluorescent polymerase chain reaction (QF-PCR) is a reliable, rapid, and economic technique for prenatal diagnosis of the most common abnormalities. However, conventional karyotyping is expensive and requires a much longer time to yield results. It is currently under debate whether the replacement or restriction of karyotyping reduces the quality of prenatal test results. This study was undertaken to determine the percentage of clinically significant chromosomal abnormalities that would not be detected if QF-PCR was the main analysis method and karyotyping reserved for cases with increased nuchal translucency (NT) and/or abnormal ultrasound findings and to estimate the difference in cost between QF-PCR and full karyotyping. METHODS: Nine hundred twenty-eight pregnant women underwent an invasive procedure at our center between May 2009 and December 2012, yielding 580 (62.5%) chorionic villous samples and 348 (37.5%) amniotic fluid samples. Samples were studied by both QF-PCR and full karyotyping. Karyotyping and detailed ultrasound findings were retrospectively analyzed. RESULTS: If QF-PCR was the main analytic method and full karyotyping reserved for cases with elevated NT (≥4.5) and/or abnormal ultrasound findings, 12.7% of the patients would have required full karyotyping, 99% of the clinically significant chromosomal abnormalities would have been detected, and the cost would have been 54% lower than a policy of full karyotyping for all. CONCLUSIONS: Detailed prenatal ultrasound scan can reduce the need for conventional karyotyping as a complement to QF-PCR in most prenatal samples, offering rapid results and reducing parental anxiety and healthcare costs.

Effects of aminobisphosphonates and thiazides in patients with osteopenia/osteoporosis, hypercalciuria, and recurring renal calcium lithiasis.

OBJECTIVE: To analyze the effects of aminobisphosphonates and thiazides on renal lithogenic activity and bone mineral density in patients with recurring renal calcium lithiasis. MATERIALS AND METHODS: A prospective cohort study with 3 years of clinical follow-up data was performed. The study included 2 groups of patients with recurring calcium lithiasis, hypercalciuria, and bone mineral density loss. Group 1 included 35 patients who underwent treatment with 70 mg/wk alendronate. Group 2 included 35 patients who underwent treatment with 50 mg/d hydrochlothiazide and 70 mg/wk alendronate. Biochemical analysis was performed at baseline, 6 months, and 2 years, bone densitometry at baseline and 2 years, and clinical follow-up during the 3 years of treatment. The biochemical variables from the blood and urine samples, recurrent lithiasis, and bone mineral density were analyzed. RESULTS: Age, sex, baseline biochemical markers, and bone density showed no differences between the 2 treatment groups at the onset of treatment. After 2 years of treatment, group 1 showed a significant decrease in bone turnover markers and calciuria and significant improvement in bone mineral density. After 2 years of treatment, group 2 showed a decrease in calciuria and bone markers. At 2 years, the decrease in calciuria and the improvement in bone mineral density were greater in group 2 than in group 1, and the difference was statistically significant. CONCLUSION: Aminobisphosphonates improve bone mineral density and slow lithogenic activity; however, administration of aminobisphosphonates in association with thiazides produced the same clinical effects and also reduced calciuria and improved bone mineral density.

Metabolic-mineral study in patients with renal calcium lithiasis, severe lithogenic activity and loss of bone mineral density.

INTRODUCTION: This study assessed the presence of osteoporosis/osteopenia in patients with severe lithogenic activity and compared their metabolisms with those in patients without lithiasis or with mild lithogenic activity. METHODS: From a sample of 182 patients, those with osteopenia/osteoporosis at the hip and lumbar spine were studied separately in a two-pronged study. 66 patients with bone mineral densities (BMDs) < -1 standard deviation (SD) on a T-score scale at the hip were divided into three groups: group A1 without lithiasis (n = 15); group A2 with lithiasis and mild lithogenic activity (n = 22); and group A3 with lithiasis and severe lithogenic activity (n = 29). Similarly, 86 patients with BMDs < -1 SD on a T-score scale at the lumbar spine were divided into three groups: group B1 without lithiasis (n = 15); group B2 with lithiasis and mild lithogenic activity (n = 29); and group B3 with lithiasis and severe lithogenic activity (n = 42). RESULTS: Patients from group A3 exhibited significantly higher levels of bone remodelling markers as compared to groups A1 and A2. Urinalysis also revealed higher excretion of calcium in 24-hour assessments in this group. Patients from group B3 differed from groups B1 and B2 mainly in bone remodelling markers and 24-hour urinary calcium excretion, which were significantly elevated in patients from group B3. CONCLUSION: Patients with calcium lithiasis and severe lithogenic activity in addition to osteopenia/osteoporosis present with higher levels of hypercalciuria and negative osseous balance, which possibly perpetuate and favour lithiasic activity.

Biochemical determinants of severe lithogenic activity in patients with idiopathic calcium nephrolithiasis.

OBJECTIVE: To analyze the biochemical alterations in plasma and the urine determinants of severe lithogenic activity in patients with idiopathic calcium nephrolithiasis. METHODS: We performed a cross-sectional study of 120 patients divided into 2 groups: group 1, 60 patients without nephrolithiasis; and group 2, 60 patients with severe and/or recurrent calcium nephrolithiasis. In all patients, a study of renal function, calcium metabolism, and bone remodeling markers, and a study of the lithogenic factors were performed in urine after fasting and in 24-hour urine samples. RESULTS: We observed greater values for phosphorus in group 1 than in group 2 (P=.03). Also, we found greater values for intact parathyroid hormone (P=.01), osteocalcin (P=.000), and ß-crosslaps (P=.000) in group 2 than in group 1. In the 24-hour urine samples, significant differences were found between groups 1 and 2 in calciuria (11.7 vs 17.4 mg/dL; P=.000), citraturia (50.6 vs 33.5 mg/dL; P=.002), calcium/creatinine quotient (0.14 vs 0.20; P=.001), calcium/citrate quotient (0.05 vs 0.13; P=.04), and calcium/creatinine quotient after fasting (0.09 vs 0.16; P=.000). CONCLUSION: We consider the determinants of severe and/or recurrent calcium lithiasis to be hypercalciuria and hypocitraturia and a calcium/citrate quotient>0.06. As risk markers we can consider phosphatemia<2.9 mg/dL, phosphate/chlorine quotient>35, alkaline phosphatase>80 U/L, intact parathyroid hormone>60 pg/mL, osteocalcin>16 ng/mL, ß-crosslaps>0.400 ng/mL, and ß-crosslaps/osteocalcin quotient>0.028.

Mineral density and bone remodelling markers in patients with calcium lithiasis.

UNLABELLED: What's known on the subject? and What does the study add? Hypercalciuria is related with bone mineral density loss. This study demonstrates the relationship between recurrent calcium nephrolithiasis and bone mineral density loss and their correlation with bone markers. OBJECTIVES: • To show that a relationship exists between the loss of bone mineral density (BMD) and calcium renal lithiasis and that bone remodelling markers correlate with changes in BMD. • It is possible that many cases hypercalciuria are related to the increase of bone turnover and the predominance of bone resorption phenomena. PATIENTS AND METHODS: • The present study comprised a transversal investigation in three groups: group O, without lithiasis; group A, with a single episode of lithiasis; and group B, with relapsed calcium renal lithiasis. • An analysis was made of body mass index; abdominal X-ray and/or urography and renal ultrasonography; osteocalcin and ß-crosslaps bone markers; calcium and citrate concentrations in the urine; and femur and spinal column bone densitometry. • The results were analyzed by analysis of variance and Pearson's correlation coefficient. RESULTS: • Patients with relapsed calcium renal lithiasis present a greater BMD loss than those in the O or A groups. • Densitometry: T-score femur -0.2 group O, -0.5 group A, -1.2 group B (P= 0.001); T-score column -0.6 group O, -0.6 group A, -1.3 group B (P= 0.05). • A statistically significant negative correlation exists between values of ß-crosslaps and T-score femur (R=-0.251; P= 0.009) and T-score column (R=-0.324; P= 0.001); thus, a higher concentration of ß-crosslaps was accompanied by a lower value of the T-score and a greater loss of BMD. • A positive relationship is observed between ß-crosslaps and osteocalcin (R= 0.611; P < 0.001) and between calciuria and cocient ß-crosslaps/osteocalcin (R= 0.303; P= 0.001). CONCLUSIONS: • A statistically significant relationship is shown between the loss of BMD and relapsed calcium renal lithiasis. • Determination of bone remodelling markers (i.e. osteocalcin and ß-crosslaps) facilitates the diagnosis of osteopaenia/osteoporosis in these patients.

Squamous cell carcinoma of the penis with rhabdoid features.

A 76-year-old man presented with a tumoral lesion in his penis that had all the light microscopic and immunohistochemical features of a squamous cell carcinoma with rhabdoid phenotype. We believe that this is the fourth reported case of squamous cell carcinoma with rhabdoid features and the first one located in the penis. Rhabdoid cells were primarily located in areas with an alveolar pattern, most of them being isolated and intermixed with necrotic cells and necrotic debris. We suggest that the rhabdoid phenotype could represent a type of degeneration, or a preliminary stage before apoptosis or cell necrosis, instead of a specific differentiation. In extrarenal tumors with rhabdoid features, stage and histologic types of tumors where rhabdoid changes occur are the most important prognostic factors.