RU2454181C1 - Method of diagnosing stage of urinary bladder cancer invasion - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, namely to urology and oncology. In order to diagnose stage of urinary bladder cancer invasion UBC-antigen of urinary bladder cancer, representing soluble fragment of cytokeratins 8 and 18, is determined in patient's urine. If its value is higher than 22.5 mcg/ml, TPS-tissue polypeptide spherical, which represents fragment of cytokeratin 18, is determined in blood serum. If TPS value is 61.5-106.93 Units/l, muscular-non-invasive urinary bladder cancer is diagnosed. If TPS value is 106.94-181.29 Units/l, invasive urinary bladder cancer within the organ is diagnosed. If TPS value is higher than 181.29 Units/l, outlet of tumour beyond the organ is diagnosed.

EFFECT: method makes it possible to diagnose stages of urinary bladder cancer invasion with high accuracy.

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Description

The invention relates to medicine, namely to urology and oncology, and is intended to clarify the stage of bladder cancer in the preoperative period.

Establishing the stage of invasion of bladder cancer is an important aspect of diagnosis, since it is this indicator that determines the choice of surgical treatment tactics and the prognosis of the disease for the patient. Non-invasive stages of cancer during the spread of the tumor within the mucous and submucosal layers allow radical surgery to be performed using the endoscopic method (transurethral resection). The invasive stages of bladder cancer have the only radical method of surgical treatment - radical cystectomy followed by diversion of urine into the intestinal reservoir.

With a correctly established stage of invasion, with Ta-T1 stage of bladder cancer, transurethral resection of a bladder tumor gives good results and allows five-year survival in 85-94% of patients. Postoperative mortality in this type of surgical treatment of bladder cancer is zero, the total number of complications is about 18%, including bleeding (6.3%), intraperitoneal perforation (0.5%), urethral stricture (7.8%). In most patients, disability is fully restored (Lopatkin N.A., Darenkov S.P., Chernyshev I.V., Martov A.G., Stupak N.V. Diagnosis and treatment of bladder cancer. "Urology", No. 1, 2004, p. 12-17).

Invasive forms of bladder cancer in urological clinics in Russia are found in 58% of patients. Compared to non-invasive forms of cancer, five-year survival in these patients is significantly lower. So, with bladder cancer with invasion through the entire wall, five-year survival is only 7-15%. Currently, cystectomy is considered as the only radical treatment. Mortality in radical cystectomy ranges from 2.5% to 26%. In the postoperative period, immediate complications are: infection in the wound, intestinal obstruction, failure of anastomotic sutures, peritonitis, sepsis, acute pyelonephritis, pneumonia, which make up an average of 10%. Thrombosis and embolism occur in 5% of the operated. At a distant postoperative stage, complications include the development of strictures in the anastomotic zone, the formation of urodynamic disorders of the upper urinary tract, pyelonephritis, hyperchloremic acidosis, chronic renal failure, impotence, and urinary incontinence. The quality of life of patients is significantly reduced and most of them receive disabilities (Lopatkin N.A., Darenkov S.P., Chernyshev I.V., Sokolov A.E. et al. Radical treatment of invasive bladder cancer. "Urology", 2003 No. 4, p. 3-7).

In this regard, the correctness of establishing the stage of invasion of bladder cancer at the preoperative stage is an extremely important task. Inconsistency of the chosen type of surgical treatment of the stage of tumor invasion leads, on the one hand, to non-observance of radicalism, and on the other hand, to the use of an unreasonable volume and severity of the surgical operation.

Difficulties in diagnosing the stage of invasion of bladder cancer are associated with the complexity of imaging and obtaining complete histological material of the tissue of the base of the tumor where, in fact, invasive growth occurs. Despite the presence of such highly informative research methods as computed and nuclear magnetic resonance imaging, the mismatch between preoperative and postoperative diagnoses is significant. An error in establishing the stage of invasion of bladder cancer occurs in 73% (Mikich D.Kh. Organ-preserving treatment for invasive bladder cancer. Oncourology. 2005, No. 2. - p. 27-32). In instrumental diagnostics, tissue sampling for histological examination is performed by transurethral access either from the surface of the tumor, which does not answer the question of the stage of invasion, or by fragmenting and coagulating the tumor tissue during transurethral resection, which reduces the information content of the study.

A known method for diagnosing the stage of invasion of bladder cancer using transurethral tumor resection. At the first stages of the procedure, exophytic tumor tissue is resected. Next, a phased removal of parts of the tumor along with its base is performed. At the final stage, a biopsy is performed with a resection of the bladder wall in the immediate vicinity of the tumor. During the procedure, wash water with fragments of tumor tissue is collected in a vessel with subsequent filtration. The resulting tissue fragments are the subject of histological examination. According to the literature, the frequency of false-negative results with respect to muscle invasion or invasion of the near-bubble tissue reaches 30-40% (Kogan M.I., Perepechay V.L. Modern diagnostics and surgery of bladder cancer. Rostov-on-Don: 2002, p. 57-58). Difficulties of morphologists are caused by tissue fragmentation and coagulation necrosis. The disadvantages of this method is the large error of the method, significant damage to the histological material due to fragmentation and coagulation. Since transurethral resection combines elements of not only diagnostic but also therapeutic procedures, it is an invasive procedure requiring general anesthesia (Pereverzev L.S., Petrov S.N. Bladder tumors. - Kharkov: Fact, 2002, p. 110 -112). In the postoperative period, complications are possible: macrohematuria, dysuria, cystitis, urethral fever, as well as the possible implantation of tumor cells on adjacent walls of the bladder.

A known method for diagnosing the stage of invasion of bladder cancer at the preoperative stage. When implementing the method, transrectal ultrasound is performed using an ultrasound transducer with a biopsy attachment mounted on it. Under the control of an ultrasound transducer, a biopsy of the base of the bladder tumor is performed through the wall of the rectum (A.S. 2332168).

The disadvantages of the method include its invasiveness, infection from the rectal ampoule, which requires additional antibacterial treatment and surgery for 3-4 weeks. It should be especially noted that it is safe to take a biopsy in this way only from the neck of the bladder, which is located to the rectum and prostate, located extraperitoneally. Other parts of the bladder: the bottom, top and side walls in the filled position are covered with the peritoneum and come into contact with the organs of the abdominal cavity by the intestines. When taking a biopsy from these sections of the bladder, damage to the intestinal loops is possible with the development of such a formidable complication as peritonitis.

A known method for the diagnosis of bladder cancer using the tumor marker UBC (antigen of cancer of the bladder), which is a soluble fragment of cytokeratins 8 and 18 (Sergeeva NS, Marshutina N. B. "Clinical significance of serological tumor markers"; magazine Together against cancer. Doctors of all specialties. - 2008, No. 2, pp. 10-21). With proliferation and malignant transformation of cells, the expression of cytokeratins increases. A patient with suspected bladder cancer is taken a morning average dose of urine for examination to determine the content of the UBC tumor marker by the method of enzyme-linked immunosorbent assay, the tumor marker level, expressed in μg / ml, is converted to creatinine level in the same urine (μmol / ml). With a UBC value higher than 4.9 μg / μmol CREA, bladder cancer is diagnosed.

The disadvantages of the method include its lack of specificity due to the fact that this indicator includes the value of creatinine in the urine, which can vary significantly with various pathological and functional conditions of the kidneys, which introduces an additional error in the diagnosis of bladder cancer. In addition, according to the authors themselves, the level of UBC can increase with such non-oncological diseases as cystitis, polyps and papillomas of the bladder, urolithiasis, bacterial infection of the urinary tract during an exacerbation, inflammatory neurological diseases. It is known that bladder cancer is very often accompanied by cystitis, and the higher the stage of the disease, the more often inflammation of the bladder occurs. In addition, this method is not stadiospecific, since the level of UBC can increase both in case of multiple muscular non-invasive tumors of the bladder, as well as in deep invasion. The quantitative indicators of UBC levels for various stages of bladder cancer have also not been determined. All this leads to diagnostic errors in establishing the stage of invasion of this cancer.

The closest is the diagnostic method developed by N. Shakhnazyan. (abstract of the dissertation “The importance of tumor markers, growth factors, angiogenesis and apoptosis in the diagnosis of superficial bladder cancer”, Saratov, 2010). The author investigated urinary UBC values in patients with bladder cancer, which was higher than 22.5 μg / ml in a patient with a sensitivity of 80%. The author investigated the values of TPS (tissue specific polypeptide antigen), which is a fragment of cytokeratin 18 in blood serum. It was found that with a TPS of more than 61.5 U / L, a patient with a sensitivity of 80% has bladder cancer, however, the study does not address the question of determining the stages of bladder cancer using tumor markers.

Thus, in no work quantitative indicators of the boundaries of the various stages of invasion of bladder cancer, TPS (tissue specific polypeptide antigen), which is a fragment of cytokeratin 18, specially designated as a tumor marker, were determined.

The objective of the invention is the preoperative determination of the stages of invasion of bladder cancer.

We first developed a method for the preoperative determination of the stages of bladder cancer, which is non-traumatic, non-invasive and not causing complications,

The essence of the method lies in the fact that a patient with suspected bladder cancer is taken urine for examination to determine the content of the bladder cancer antigen (UBC tumor marker) using an enzyme-linked immunosorbent assay, which is a soluble fragment of cytokeratins 8 and 18. Method for determining the level of tumor marker performed using the UBC II ELISA reagent kit (manufacturer IDL Biotech AB (Sweden)), and, according to the instructions supplied by the manufacturer with the kit, the UBC level is displayed in micrograms per milliliter liter of urine.

When the UBC tumor marker value is higher than 22.55 μg / ml, blood serum is taken from the same patient for determination in it by TPS (Tissue Polypeptide Antigen Specific) enzyme-linked immunosorbent assay, which is a fragment of cytokeratin 18. The oncomarker level is determined using using the TPS ELISA reagent kit (manufacturer IDL Biotech AB (Sweden)), and, according to the instructions supplied by the manufacturer with the kit, the TPS level is displayed in units (U) per liter of blood serum. With a TPS tumor marker of 61.5-106.93 U / L, the patient is diagnosed with muscle-non-invasive bladder cancer (Ta-T1). When the content of the tumor marker TPS is 106.94-181.29 U / L, the patient has invasive bladder cancer within the organ (T2a-T3a). If the values of the TPS marker are higher than 181.29 U / L, then the patient ascertains the tumor exit beyond the limits of the organ (extraorgan - T3b-T4). The boundaries of the values of the TPS level at various stages of bladder cancer were calculated using ROC analysis with the determination of the coordinates of the points of the characteristic curve that displays marker levels with optimal diagnostic characteristics.

By our proposed method, 72 patients were examined, of which 61 patients had a preoperative diagnosis established using the TPS tumor marker that coincided with a postoperative one (84.7% accuracy). In the group of patients with muscle-non-invasive bladder cancer, the preoperative diagnosis coincided with the postoperative in 29 of 32 patients (90.6% accuracy); in the group of patients with invasive cancer within the body, the coincidence of diagnoses in 20 out of 27 patients (accuracy 74.1%); in the group of patients with extraorganic cancer, a coincidence was found in 12 of 13 people (accuracy 92.3%). The results are displayed in the table.

Preoperative marker diagnosis (the proposed method) Oncomarker (TPS) Unit / L Postoperative diagnosis Accuracy Ta-T1 29 people 61.5-106.93 Ta-T1 - 32 people 90.6% T2a-T3a 20 people 106.94-181.29 T2a-T3a - 27 people 74.1% T3b-T4 - 12 people > 181.29 T36-T4 - 13 people 92.3%

Based on the statistical analysis by the Mann-Whitney criterion, significant differences in TPS values were established in the groups between non-invasive (Ta-T1) and invasive (T2a-T3a) (p 0,000356), as well as between the group of patients with invasive (T2a-T3a ) and extraorganic bladder cancer (T3b-T4) (p 0.000859).

Example No. 1

Patient T., 40 years old (medical history No. 2830), was admitted to the urology clinic of the SSMU on March 20, 2008 with complaints of a periodic admixture of blood in the urine. He considers himself sick over the past 1.5 months, when he first noticed an admixture of blood in the urine for no apparent reason. He turned to a urologist in a polyclinic, where after performing a CT scan of the kidneys, microliths were found in the middle and lower cups of the left kidney. The diagnosis of urolithiasis, microliths of the left kidney, chronic calculous pyelonephritis. The patient was prescribed treatment: 5-NOC, cyston, which had a short-term effect, since hematuria was repeated. 02/18/2008, the patient underwent ultrasound of the kidneys and bladder, in which microliths were confirmed in the left kidney of 6 and 5 mm, but a volume formation of 35 × 24 mm in size on the right wall was found in the bladder. On March 7, 2008, the patient underwent CT of the pelvic organs, in which no convincing data on the formation in the bladder were obtained.

Survey and excretory urography: There are no shadows of calculi. The excretory function of the kidneys is preserved, the necks of the cups on the right are somewhat enlarged, the volume of the pelvis on the right is greater than on the left. The shadow of the bladder is deformed, has a filling defect on the right wall with a diameter of about 3 cm. There is no residual urine. Conclusion: Tumor of the bladder.

Before the production of the instrumental study, the tumor markers were taken for the patient: UBC - 68.97 μg / ml, TPS - 103 U / ml. Based on the method we developed, a non-invasive muscle cancer of the bladder was established before surgery.

Cystoscopy: Urethra freely passable, residual urine 10 ml, urine without impurity of blood. The bladder capacity is 250 ml, the mucosa is pale pink. The mouths of the ureters at 5 and 7 hours are slit-like. Above the right orifice, 1 cm villous tumor 2 × 3 cm on a thin stalk. Tumor biopsy taken.

Histological conclusion No. 2677-2684: Against the background of urothelial papilloma, there are focuses of growth of non-invasive urethelial bladder cancer of low malignancy. Clinical diagnosis made: Bladder cancer T1NoMoG1.

03/21/08, the operation was performed transurethral electroresection of the right side wall of the bladder along with a tumor with intravesical chemotherapy with mitomycin 40 mg. In the postoperative period, there were no complications, and on April 7, 2008, the patient was discharged from the hospital under the supervision of an oncologist and urologist with cystoscopic control once every three months.

In this example, it was shown that radiation methods for the diagnosis of ultrasound, CT and excretory urography had conflicting data. So, with ultrasound and excretory urography, a tumor was detected, but the results of a seemingly more advanced computer study of the tumor were excluded. Our proposed method made it possible not only to diagnose bladder cancer, but also to establish the stage of its invasion, which was confirmed by postoperative histological examination.

Example No. 2

Patient R., 60 years old, medical history No. 711, was sent to a urology clinic with a diagnosis of bladder cancer T2-3NoMo ureterohydronephrosis on the left, in the direction of the city oncology clinic. From the anamnesis, it was found that on August 15, 2009, in one of the urological departments, transurethral electroresection of a bladder tumor was performed in connection with macrohematuria. Histological examination of the removed tumor revealed transitional bladder cancer. In the preoperative period, marker diagnostics were not performed. Ultrasound examination of the upper urinary tract revealed ureterohydronephrosis on the left. This circumstance was regarded as invasion of a tumor of the bladder of the mouth of the left ureter. Based on this, the patient was diagnosed with muscle-invasive bladder cancer, and he was referred to the urology clinic for radical cystectomy.

When examining urine and blood for tumor markers, it was found that UBC is 10.2 μg / L, TPS - 51 U / L. These indicators, according to the proposed method, indicate that the patient does not have bladder cancer. Therefore, the diagnosis of muscle-invasive bladder cancer was in doubt, the examination was continued.

When magnetic resonance imaging of the pelvic organs in the projection of the bottom of the bladder marked area of infiltrative changes of 3 × 2 cm at the site of the former transurethral resection. On the survey urogram in the lower third of the left ureter, a contrast shadow of 0.5 × 0.7 cm was detected. When performing excretory urography over this shadow, there is a stasis of contrast medium, which indicates the presence of stone in the lower third of the left ureter.

The patient underwent photodynamic cystoscopy: in which the capacity of the bladder is 250 ml. Behind the ureteric ligament, in the bottom area there is a scab in the form of white-gray tissues after electroresection of the bladder wall together with the tumor. After removal of necrotic tissue from the bed of the removed tumor, a biopsy was taken. No histological examination of the biopsy specimen revealed cancer cells. There was no pathological glow during photodynamic diagnosis both at the resection site and in other parts of the bladder. Along with diagnostic studies, the patient underwent contact lithotripsy of the left ureter stone. The postoperative period was uneventful.

Thus, laboratory marker diagnostics prevented diagnostic and tactical errors, exclude the presence of bladder cancer at the time of taking material for TPS research. Thus, instead of cystectomy, the patient underwent organ-preserving treatment. Within 9 months of monitoring the patient after treatment of relapse of a tumor of the bladder was not detected.

In this example, the accuracy of our proposed method was higher than MRI.

Example 3

Patient R., 44 years old (medical history No. 303), was admitted to the urology clinic of the SSMU on March 1, 2007 with a diagnosis of "bladder neoplasm." On admission, he complained of a periodic admixture of blood in the urine, frequent urination. Ultrasound of the urogenital organs revealed two volumetric formations of 4 × 5 × 6 cm and 2 × 2 × 2.3 cm in the bottom and right side walls of the bladder. Pathological changes in the pyelocaliceal system of the kidneys were not detected. On the survey urogram, shadows of stones are not determined. The shape and position of the kidneys is normal, contrast is distinguished in a timely manner. Cavities of the pyelocaliceal system are not expanded, they have the usual configuration. The ureters are passable on both sides, have a normal course and caliber. The bladder is homogeneous, the contours are clear, deformed due to pressure along the lower office. Residual urine control - about 80 ml. Conclusion: Prostatic hyperplasia.

On the magnetic resonance imaging of the pelvic organs, the bladder contains a moderate amount of urine. Its walls are unevenly thickened, the shape is irregular. A solid volume formation, with a wide base adjacent to the bubble wall and growing from it, with uneven fuzzy contours, of an inhomogeneous structure, is defined in the region of the bottom on the left. The wall of the bubble in the area of education is thickened, retracted. The growth of the neoplasm beyond the walls of the organ is not determined. The dimensions of the formation are 4.7 × 4.6 × 6.0 cm. A similar formation of 1 × 2.5 × 2.3 cm and a smaller formation with dimensions of 1.3 × 0.6 × 1.2 are determined from the right side wall of the bubble see. Inguinal lymph nodes are visualized up to: on the right, 0.9 × 0.5 cm, on the left, 1.3 × 0.7 cm. Conclusion: MRI picture of neoplasms of the bladder.

Urine and blood were taken at tumor markers. The urinary UBC level was 25.45 mcg / ml. TPS of blood - 177.65 U / L. With cystoscopy: a bladder capacity of 300 ml. On the right side wall, a non-villous papillary mass is seen, located from 10 to 6 hours. On the left and back walls are two similar formations with a diameter of 2.5 and 1.5 cm. A biopsy was taken from all neoplasms. Histological findings: Non-invasive urethral bladder cancer with low malignancy potential.

Based on the increase in TPS that is characteristic of muscle-invasive bladder cancer and MRI data, a diagnosis was made of urethral bladder cancer T2NxMo. A radical cystectomy was performed. Histological postoperative diagnosis: Urothelial cancer of the bladder T2bN1Mo G1 with infiltration of the entire muscle layer. In the iliac lymph node metastasis of ureterial bladder cancer.

In this example, our proposed method was more accurate than preoperative histological examination of the tumor. This allowed the patient to choose the appropriate treatment tactics of the appropriate stage. Otherwise, all other treatments would be palliative.

Thus, as can be seen from the description and the above examples, our proposed method of preoperative diagnosis has high accuracy in determining the stage of bladder cancer, which allows us to choose an adequate treatment method and improve the long-term results of treatment for this category of patients.

Claims (1)

A method for diagnosing the stage of invasion of bladder cancer, including the determination in the urine of a patient with UBC - an antigen of bladder cancer, which is a soluble fragment of cytokeratins 8 and 18, characterized in that if it is higher than 22.5 μg / ml, TPS - tissue is determined in blood serum a specific polypeptide, which is a fragment of cytokeratin 18, and with its value of 61.5-106.93 units / l, muscle-non-invasive cancer of the bladder is diagnosed, with a value of 106.94-181.29 units / l - invasive bladder cancer bubble within the body, and when uu it above 181.29 u / l diagnose a tumor out of the body outside.