Suspicious urine cytology (class III) in patients with bladder cancer: should it be considered as negative or positive?

OBJECTIVES: Urine cytology is the gold standard in the diagnosis and follow-up of bladder cancer. Cytology, however, exhibits variable sensitivity depending on tumour grade and interpretation of urine specimens is highly dependent on the skill of the examiner. Positive cytology, classes IV and V by Papanicolaou classification, is a strong predictor for coexisting or subsequent malignancy, while the role of suspicious cytology, class III, is controversial. The objective of the study was to evaluate the role of the suspicious finding in cytological analysis, and whether it should be considered as a negative or positive sign for coexisting malignancy. MATERIAL AND METHODS: Six hundred and fifty-two consecutive patients with bladder cancer were studied in a prospective multicenter trial. One hundred and fifty-one of the patients were newly diagnosed, and the remaining 501 patients were under follow-up. A voided urine sample was obtained prior to TURB or prior to routine follow-up cystoscopy in those under the surveillance and split for culture and cytology. The cytopathological results were analyzed by a central review and only patients with samples available for review analysis were included. Sensitivity and specificity, as well as positive (PPV) and negative (NPV) predictive values of urine cytology were calculated by classifying the class III samples as negative or positive. RESULTS: A total of 570 patients were evaluable. One hundred and twenty nine (22.6%) were newly diagnosed and 441 were under follow-up, of whom 117 (26.5%) had recurrence. Cytology was classified as suspicious in 33/129 (25.6%) patients with primary tumour, and in 41/441 (9.3%) of those under the follow-up, of whom 20 (48.8%) had recurrence. Sensitivity increased from to 31.0% to 56.6% in primary tumours (p < 0.001) and from 17.8% to 34.7% in recurrent tumours (p < 0.001) if class III was determined as positive, whereas the specificity decreased from 96.6% to 90.1% (p < 0.001). Accordingly, the NPV increased from 76.3% to 79.1% and the PPV decreased from 65.6% to 56.2%. CONCLUSIONS: The poor sensitivity of voided urine cytology improved significantly when suspicious samples were determined as positive while the specificity remained high, a clear advantage compared with most of the new tumour marker tests. In addition, nearly half of the follow-up patients with suspicious class III cytology had recurrence implying that this patient category is at substantial risk for co-existing malignancy. Therefore, it is recommended that suspicious class III cytology together with class IV and V specimens should be considered positive.

The dilemma of suspicious urine cytology in patients being followed for bladder cancer.

BACKGROUND AND AIMS: Urine cytology is gold standard for clinical tests used in the diagnosis and follow-up of bladder cancer. Cytology, however, exhibits variable sensitivity depending on tumour grade and interpretation of urine specimens is highly dependent on the skill of the examiner. Furthermore, a "suspicious" cytology report (class III) makes clinicians uncomfortable. In these cases, a more objective test, such as the BTA stat Test, may be useful in providing clarification. The aim of this study was to evaluate the dilemma of suspicious routine urine cytology and to determine whether the BTA stat Test provides diagnostic aid in this rare but controversial category. MATERIAL AND METHODS: 506 consecutive patients who were being followed for bladder cancer were included in the study. A voided urine sample was obtained prior to routine follow-up cystoscopy and split for culture and testing with the BTA stat Test. Clinical status of the disease was evaluated in patients with suspicious urine cytology, and the diagnostic aid of the BTA stat Test in these patients was determined. RESULTS: A total of 57 patients (11.3%) had urine cytology classified as suspicious. The BTA stat Test was positive in 29 (50.9%) and negative in 28 (49.1%) patients. Nineteen (33.3%) patients had recurrence at routine cystoscopy. Of the remaining 38 patients, 10 were further investigated due to a positive BTA stat Test. Two additional recurrences were detected bringing the total number of recurrences to 21 (36.8%), 48.3% (14/29) of the patients with positive and 25.0% (7/28) of the patients with negative BTA stat Test had recurrence (p = 0.069). Overall, 65.5% (19/29) of the patients with a positive BTA stat Test were found to have recurrence either at routine cystoscopy, at further investigations, or at the next cystoscopy compared to that of 35.7% (19/28) in those with negative testing (p = 0.024). The overall sensitivity of the BTA stat Test was 66.7%, and the specificity was 58.3%. CONCLUSIONS: At least a third of the patients under follow-up for bladder cancer with suspicious cytology had a recurrence, indicating that these patients are a risk group for recurrence. More importantly, a BTA stat Test result seems to provide some help in distinguishing those patients with very high risk for recurrence, for whom invasive further investigations should be conducted and a close follow-up policy maintained.

Ulcer perforation in gastric urinary conduit: never use a gastric segment in the urinary tract if there are other options available.

A male patient, who had had a conservatively treated hemorrhagic peptic ulcer 12 years earlier, underwent gastrocystoplasty after radical cystoprostatectomy for carcinoma of the urinary bladder. After operation the patient suffered urinary incontinence and dysuria which he found so bothersome that the gastric bladder was converted to diversion using the same gastric segment as a tube. Postoperatively there were clots of blood in stomal urine and after the kidneys had been drained intestinal fluid oozed from the stoma. On the 14th postoperative day the patient died of pulmonary embolism. The autopsy showed a perforated peptic ulcer in the gastric segment resulting in a closed fistula to the small bowel. Most probably the reason for development of the peptic ulcer was stress caused by the operation and it might have been avoided by using hydrogen-blocking agents. This case seriously questions whether a gastric segment should be used in the urinary tract at all, and at least it should never be used as a conduit.

Primary malignant melanoma of the urinary bladder associated with widespread metastases.

Malignant melanoma in the urinary tract is very rare. Tumours found in the urinary bladder are usually metastatic. Some ten cases of primary malignant melanoma have been described in the literature, and in only a few of those has a primary bladder melanoma with many distant metastases and rapid fatal outcome been reported. For the first time in Finland, we present a case of primary malignant bladder melanoma associated with widespread metastases.

Concomitant i.v. and oral clodronate in the relief of bone pain--a double-blind placebo-controlled study in patients with prostate cancer.

Fifty-seven patients with advanced prostate cancer resistant to first-line hormonal therapy were treated with estramustine and additionally randomized for treatment with clodronate or placebo. Clodronate treatment was started with 5 days intravenous administration (300 mg day[-1]) and followed by oral treatment (1.6 g day[-1]) for 12 months. Skeletal pain relief was only about 10% better in the clodronate than in the placebo group. The results do not support the superiority of combined intravenous and oral treatment with clodronate compared with oral administration only.

Effect of concomitant administration of clodronate and estramustine phosphate on their bioavailability in patients with metastasized prostate cancer.

Estramustine phosphate is generally used as a second-line treatment in patients with advanced prostate cancer. The bone metastases due to the cancer are often treated simultaneously with clodronate in order to relieve the bone pain. Therefore, the interaction of clodronate (800 mg orally four times daily) and estramustine phosphate (280 mg orally twice daily) on their bioavailability was studied in twelve patients with prostate carcinoma and bone metastases. The drugs were first given separately, each to six patients, for five days, and then concomitantly for the same period. The bioavailabilities of the drugs were calculated on the last day of each treatment period. When clodronate was given alone, its concentrations in serum and AUC for one dose interval (6 hr) did not differ from those obtained with the drug given concomitantly with estramustine phosphate, nor did the combination of estramustine phosphate change the excretion of clodronate in urine. The serum concentrations of estramustine phosphate were elevated by about 80% when the drug was given together with clodronate. The AUC for one dose interval (12 hr) was also significantly higher for estramustine phosphate with clodronate than without clodronate. The urinary excretion of estrone, a major metabolite of estramustine phosphate, was also significantly higher after the admission with clodronate. The results suggest that clodronate increases the oral bioavailability of estramustine phosphate.

Type I collagen degradation product (ICTP) gives information about the nature of bone metastases and has prognostic value in prostate cancer.

Although osteosclerotic bone metastases are characteristic of prostate cancer, mixed metastases with a lytic component are not uncommon. Type I collagen is synthesised by osteoblasts and accounts for about 90% of the organic matrix of bone. We have used new specific immunoassays for PICP (carboxy-terminal propeptide of type I procollagen) and ICTP (cross-linked carboxy-terminal telopeptide of type I collagen) which allow simultaneous assessment of the synthesis and degradation of type I collagen respectively. Forty patients with bone metastases due to prostate cancer at the time of diagnosis were investigated with these methods. Twenty-three of them had sclerotic (S) and 17 had mixed metastases with sclerotic and lytic components (S + L) as assessed by radiographs. The concentrations of PICP and ICTP in serum as well as the activity of alkaline phosphatase (AP) were increased in all patients of the S + L group, who had more aggressive bone disease and a shorter survival than the S group (P < 0.017). The ICTP level was above the reference range in half of the patients in the S group, whereas the PICP and AP levels were elevated in 35%. Of the bone markers, only ICTP was of prognostic significance (P < .05). We conclude that ICTP and PICP give information about the type and activity of the skeletal metastases. In addition, ICTP predicts prognosis.

The effect of combined intravenous and oral clodronate treatment on bone pain in patients with metastatic prostate cancer.

Although osteosclerotic metastases are characteristic of prostate cancer, bone resorption is also accelerated. Clodronate is a specific inhibitor of osteoclastic bone resorption and relieves bone pain of osteolytic lesions in myelomatosis and breast cancer. The present open study included 16 prostate cancer patients who had painful bone metastases and who had failed hormonal therapy. Clodronate was given intravenously for six days (300 mg/day) followed by oral treatment for 21 days (3200 mg/day). A clear pain relief was found in nine of the 16 (56%) patients after intravenous administration. During the next three weeks with oral administration there was still pain reduction in five patients, while in three patients the pain increased. The treatment had no effect on conventional tumour markers but urinary hydroxyproline excretion decreased, indicating reduced bone resorption. Clodronate offers an alternative for treating patients with painful metastases from prostate cancer.

The effect of clodronate on bone in metastatic prostate cancer. Histomorphometric report of a double-blind randomised placebo-controlled study.

57 patients with advanced prostate cancer and a failure of prior hormonal treatment were selected for a double-blind placebo-controlled trial, in which they were randomly allocated to receive either clodronate (C) or placebo concomitantly with the basic cancer treatment, estramustine phosphate (E) (560 mg daily). The treatment was started intravenously with 300 mg of C or placebo in 5 consecutive days, and thereafter maintained orally with 1600 mg of C or identical placebo daily for 3 months. Bone biopsies were taken at admission and at 3 months. Measurements of serum calcium, phosphate, alkaline phosphatase, prostate-specific antigen and creatinine were made at the time of both bone biopsies and at 1 month. Serum intact parathyroid hormone and vitamin D metabolites were measured at admission and at 3 months. Because of several discontinuations, the study groups at final analysis comprised 20 patients taking E + C and 19 patients taking E and placebo. Bone resorption, as judged by eroded surface and osteoclast number, was markedly increased especially in biopsies taken from tumour-involved bone. Treatments with E + C or E both induced a significant decrease in bone resorption, but were associated with the development of hypocalcaemia, secondary hypoparathyroidism, hypophosphataemia and severe impairment of mineralisation of newly formed bone, i.e. osteomalacia. Since the patients were not vitamin D deficient, we conclude that osteomalacia resulted from a relative deficiency of calcium and phosphate. The transiency of pain relief achieved with anti-resorptive agents in the treatment of bone metastases from prostate cancer may be due to the development of osteomalacia.

Study of tyrosine hydroxylase and neuropeptidergic innervation of the human obstructed pelveoureteral junction in four different patients.

Tyrosine hydroxylase and neuropeptidergic innervations of the obstructed pelveoureteral junctions of four different patients were investigated by immunohistochemical methods. A dense innervation of tyrosine hydroxylase- and neuropeptide Y-nerves was found especially in the pelveoureteral junction, which was congenitally obstructed, compared to others found later (13- and 23-year old females). Also quite numerous vasoactive intestinal polypeptide-nerves were seen as well as some calcitonin gene-related peptide-, galanin- and substance P-nerves in the muscular layer of ureter. The innervation pattern of the obstructed pelveoureteral junction of the horseshoe kidney was found to be normal.

Evaluation of the effect of oral clodronate on skeletal metastases with type 1 collagen metabolites. A controlled trial of the Finnish Prostate Cancer Group.

Clodronate relieves bone pain in patients with skeletal metastases. Since the pain relieving mechanism of clodronate may be associated with the antiosteoclastic activity, we have investigated whether the drug has simultaneous actions on bone resorption and pain. Although osteosclerotic metastases are characteristic of prostate carcinoma, bone resorption is also accelerated. The resorbing process can be investigated using a specific immunoassay for ICTP (cross-linked carboxyterminal telopeptide region of type I collagen) which allows the measurement of the degradation of type I collagen in serum samples. We have also determined serum concentration of PICP (carboxyterminal propeptide of type I procollagen) which reflects the synthesis of type I collagen (osteoid). Patients who have relapsed after first-line hormonal therapy, were randomised to receive estramustine phosphate (E) with or without clodronate (C) (E + C, n = 50; E, n = 49). The dose of E was 560 mg and that of C 3.2 g for the first month, thereafter 1.6 g. We saw elevated ICTP and PICP levels in the majority of the patients. A transient decrease in ICTP values occurred simultaneously with pain relief. The changes were more accentuated in the E + C than in the E group but the difference was not significant. In each group serum phosphate concentration decreased markedly (P = 0.001) whereas the activity of alkaline phosphatase remained increased, both indicating a development of osteomalacia during E therapy. The short-term antiosteoclastic effect of C may be explained by the dose reduction, hyperosteoidosis and osteomalacia which inhibit the binding of C on the crystal surfaces and by the late phase of disease.

Effect of oral clodronate on bone pain. A controlled study in patients with metastic prostatic cancer.

Although osteosclerotic metastases are characteristic of prostatic carcinoma, bone resorption is also accelerated. Since clodronate inhibits bone resorption and relieves bone pain, we have given it to patients with painful bone disease from prostatic cancer after failure of hormonal therapy. All patients received estramustine phosphate orally. Simultaneously they were randomly allocated to clodronate (36) and placebo (39) groups. Clodronate was given by mouth. The dose was 3.2 g for the first month, thereafter 1.6 g. Pain relief was more distinct in the clodronate group where one third of patients were totally free of bone pain. The use of analgesics stopped in 38% of patients on clodronate and in 18% on placebo which effect probably belongs to estramustine phosphate. Serum calcium concentration decreased more markedly in the clodronate group. Clodronate dose of 3.2 g seemed to be more potent than that of 1.6 g. Side effects were uncommon and occurred equally in both groups. No significant differences were seen in median survival or survival rates between the groups.

Peptidergic innervation of the normal and obstructed human pyeloureteral junctions.

The neuropeptidergic innervation of the normal and obstructed human pyeloureteral junction was investigated using immunohistochemical techniques. A dense innervation of neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP) in the intrinsic obstruction type was demonstrated. NPY and VIP formed networks in the muscular layer. NPY was also found in perivascular plexuses and VIP adjacent to the epithelium. Calcitonin gene-related peptide, galanin and substance P nerves were also seen in the muscular layer, although sparsely. It is proposed that NPY and VIP have a role in the pathophysiology of the intrinsic obstruction type of the human pyeloureteral junction. The innervation pattern of the junction with the external type of obstruction was similar to that of the normal pyeloureteral junction.