The purpose of the study was to assess the frequency of bile duct confluence variations in patients with hilar cholangiocarcinoma and in patients with no biliary lesions.

Material and Methods. The study included 203 patients with Klatskin tumor (study group) and 191patients having no bile duct lesions (control group). All patients underwent abdominal MRI including MR-cholangiopancreatography. In addition, 141 patients from the study group underwent percutaneous transhepatic cholangiography. Anatomic variations of the bile duct confluence were based on Nakamura classification.

Results. In the study group, type I, II, III, IV and V confluences were detected in 27.6 %, 22.2 %, 1.5 %, 36.0 % and 2.4 % of cases, respectively. In the control group, the frequencies of each type of the bile duct confluence were as follows: type I in 75.0 %, type II in 9.3 %, type III in 0.5 %, type IV in 14.2 % and type V in 1.0 %. Differences between groups were statistically significant (p<0.001). Statistical and hydrodynamic bile duct confluence models that could explain the differences between the groups were proposed.

Conclusion. The frequency of uncommon bile duct confluences in patients with Klatskin tumor was significantly higher than that observed in patients having no biliary lesions; it might be due to a larger area of bile ducts in non-first confluence types or higher endobiliary pressure.

Introduction. Detection of bone metastases in cancer patients is of great importance in the choice of treatment tactics and assessment of the disease prognosis. The article discusses the «superscan» phenomenon on bone scintigraphy in detecting skeletal metastases in prostate cancer (PC) patients. When analyzing published reports, we found only one large prospective study and a few case report publications on the detection of «superscan» in patients with generalized skeletal involvement.

The purpose of the study was to determine the laboratory and clinical morphological parameters associated with «superscan» scintigraphic phenomenon in patients with prostate cancer.

Material and Methods. Of 2474 prostate cancer patients who underwent bone scintigraphy, 48 had the «superscan» phenomenon. Clinical, laboratory and morphological parameters were: age of the patients, tumor stage by TNM (7th edition, 2010), histological type of the tumor, Gleason index, prostate specific antigen (PSA) level, pain syndrome (on a 5-point verbal scale of pain estimates, 1982), the presence of castration-resistant prostate cancer, hemoglobin level and erythrocyte sedimentation rate (ESR).

Results. The «superscan» phenomen was found to occur most often in prostate cancer patients aged 60-69 years. Stage III and IV tumors were detected in 97.9 % of cases, lymphatic invasion in 20.8 %, and visceral metastases in 12.5 %. In addition, the phenomenon was associated with high PSA levels (the mean PSA level was 100 ng/ml, range: 26-4957) and the presence of moderately and poorly differentiated (Gleason ≥7)) tumors. Chronic pain syndrome at the time of detection of «superscan» was observed in 47.9% of patients, castration resistance - in 16.6 %. The median hemoglobin level was 114 (75-139) g/l and ESR was 34 (14-62) mm/h.

Conclusion. The most significant factors associated with the «superscan» scintigraphy phenomenon in prostate cancer patients were the primary tumor extension, high PSA level and low-grade tumors. New data on the association between the «superscan» phenomenon and the levels of hemoglobin and ESR have been obtained. Further studies on the relationship between the «superscan» phenomenon and pain syndrome and castration resistance are required.

Aim: to conduct a comparative analysis of the safety of postoperative accelerated hypofractionated radiotherapy for patients with stage I-IIIA breast cancer.

Material and Methods. From 2013 to 201, 316 patients with stage I-IIIA breast cancer were treated at A.F. Tsyb Medical Radiological Research Center. Postoperative accelerated hypofractionated radiotherapy at a single daily dose of 2.7 Gy to a total dose of 40.5 Gy was given to 223 patients. The control group patients received the conventional radiation therapy at 2 Gy per fraction to a total dose of 50 Gy (n=93). The quality of life of patients was evaluated using the questionnaire EQ-5D consisting of descriptive part and a visual analogue scale (EQ VAS).

Results. The frequency of edema of the upper limb did not depend on the fractionation regimen. This complication occurred more often in cases with axillary radiotherapy (р<0.01) and in cases with radical mastectomy. No difference in the quality of life between the patient groups was found.

Conclusion. Postoperative accelerated hypofractionated radiotherapy at 2.7 Gy per fraction to a total dose of 40.5 Gy is safe and can be used after both organ-sparing surgery and radical mastectomy. This radiotherapy regimen is more preferable than the conventional one due to the reduced treatment time. Axillary radiotherapy signifcantly increases the risk of lymphedema of the upper limb.

Quality of life of 42 patients with locally advanced breast cancer (T2-4N0-3M0) after combined modality treatment including either neutron therapy or photon therapy was studied. The EORTC QLQ-30 (version 3.0) and EORTC QLQ -BR-23 questionnaires were used. A slight decrease in the physical and emotional state and nausea/vomiting were observed in the group of patients who received neutron therapy (n=20) as well as in the group of patients who received photon therapy (n=22). In patients of the neutron therapy group, an increase in the index of dyspnea by 6 points (with the baseline index of 15.0 ± 5.7 points) was observed. The dyspnea index decreased to 5.26 ± 2.9 points 12 months later in patients having no evidence of disease progression. Local pulmonary fibrosis was diagnosed in 2 (10 %) of 20 breast cancer patients. In photon therapy group patients, an increase in the index of dyspnea by 11 points (with the baseline index of 14.3 ± 5.1 points) was observed. In 12 months, the dyspnea index decreased to 7.1 ± 3.1 points. Local pulmonary fibrosis was diagnosed in 4 (18 %) of 22 patients. A moderate decline in the general health status was observed in both groups of patients after neutron therapy delivered to the anterior chest wall. However, all patients with locally advanced breast cancer subjectively noted the rise of the general health status 12 months after completion of treatment (78.3 ± 4.2 points, respectively). Thus, postoperative neutron therapy delivered to the anterior chest wall did not increase the frequency of complications and did not affect the quality of life of breast cancer patients.

Introduction. In accordance with uICC and AJCC 8th edition TNM classifications, there is a strong evidence for division of oropharyngeal squamous cell carcinoma (OPSCC) into 2 molecular subtypes by HPV-status with distinct prognosis depending on biological differences. Such a division leads to differences in staging OPSCC and in future it will lead to implementation of preventive measures and new therapeutic strategies against HPV-positive cancer.

Aim of the study: to assess the clinical and prognostic significance of the combination of P16, a surrogate marker for HPV-positivity, and high proliferative activity in patients with oropharyngeal carcinoma.

Material and Methods. Immunohistochemical (ICH) analysis with monoclonal antibodies specific for P16 and Ki67 proteins was used to detect expression patterns in the formalin-fixed, paraffin-embedded tumor samples obtained from 104 patients with squamous cell carcinoma of the tongue and oropharynx, treated at Oncological Dispencery № 1 in Krasnodar from 2011 to 2016. HPV-positive status was determined if more than 70 % of tumor cells had moderate or strong nuclear and cytoplasmic P16-staining. High index of proliferative activity (PA) was detected if more than 50 % tumor cells expressed Ki67 nuclear antigen.

Results. P16-positivie status was associated with tonsillar cancer (р=0.002), female gender (р=0.015), age <60 years (р<0.001), non - keratinizing morphology (р=0.022), and high index of PA (p=0.01).The combination of P16>70 % with high PA demonstrated correlation with tonsillar cancer (р<0.001), female gander (р=0.015), age under 60 years (р<0.001) and non - keratinizing morphology (р=0.012). HPV-positive patients and patients with a combination of P16>70 % and high index of PA at N1-2 had an overall survival benefit (p=0.021).

Conclusion. The correlation between IHC-complex for P16>70 %/Ki67>50 % and clinicopathologicl parameters and overall survival confirms the biological features of HPV-associated cancer. The evaluation of this IHC-complex can increase the diagnostic accuracy of IHC-analysis of HPV-status and predict the prognosis of patients with OPSCC.

To improve early detection of cancer, search for tumor markers in biological fluids is of great importance. A significant portion of exosomes is associated with the surface of blood cells, however, the protein spectrum of such exosomes has not been previously studied. The use of total blood exosomes (plasma exosomes and exosomes associated with the surface of blood cells) can not only significantly increase the specificity and sensitivity of existing methods, but also suggest new tumor markers for liquid biopsy.

Objective. Search for candidate protein tumor markers of breast cancer by comparing 2D-proteomic maps of total blood exosomes of healthy females (HFs) and breast cancer patients (BCPs).

Methods. Exosomes were isolated from plasma and total blood of HFs and BCPs by ultrafiltration followed by ultracentrifugation and were characterized using transmission electron microscopy (TEM) and immunocytochemistry. Protein concentration in exosomes was determined using the NanoOrange Protein Quantitation kit (Invitrogen) commercial kit. Proteomes of exosomes were studied using 2d electrophoresis followed by protein identification by mass spectrometry.

Results. Highly purified samples of vesicles from plasma and total blood of no more than 100 nm in size were obtained, on the surface of which markers specific for exosomes were detected by monoclonal antibodies CD9. A comparative analysis of the proteomic maps of exosomal proteins of the HFs and BCPs obtained by 2D-electrophoresis allowed us to establish significant differences in the expression level and protein set in normal and pathological conditions. The 11 proteomic markers of breast cancer were identified by the peptide fingerprint method, of which LRG и у-chain FGB were detected in the composition of exosomes for the first time (according to the Exocarta database). Using MALDI-TOF mass spectrometry, 99 proteins were identified in the exosome preparations of the blood of HFs and BCPs, of which 35% were detected in the composition of the exosomes for the first time (according to the Exocarta database). 17 (53%) proteins associated with breast cancer were detected in total blood exosomes of cancer patients.

Conclusion. The results obtained indicate that total blood exosomes are a promising source of diagnostic material for the search for proteomic markers of breast cancer. The identified proteomic tumor markers require further validation.

The relationship between autoantibodies specific to estradiol (Es)/ progesterone (Pg) and the concentrations of these hormones in the blood serum of healthy women and breast cancer patients has been previously revealed.

Purpose: to study the association between anti-idiotypic antibodies to Es and Pg and the concentrations of these hormones in postmenopausal healthy women and breast cancer patients.

Material and Methods. The levels of Es and Pg in the blood serum of 206 healthy women and 480 breast cancer patients were studied using competitive enzyme immunoassay. The levels of autoantibodies to Es and Pg and appropriate antiidiotypic antibodies in the same serums were studied using non-competitive enzyme immunoassay.

Results. The high personal ratio of hormones (Pg/Es >4.0) was associated with the low breast cancer risk (OR=0.3; р<0.0001), high individual ratio of specific antibodies (IgA-Pg1/IgA-Es1>1.0; р=0.004) and high individual ratio of anti-idiotypic antibodies (IgG-Pg2/IgG-Es2>1.0; p<0.001) in healthy women, but not in breast cancer patients.

Conclusion. The association between anti-idiotypic antibodies of G class specific to Es/ Pg and hormonal status was revealed in healthy women but not in breast cancer patients. Further studies on the mechanisms of immunoregulation of carcinogenesis are needed.

Introduction. To study the antitumor effect of substances in vivo, it is necessary to create a model that reflects the main characteristics of a human disease. Patient-like xenografts (Patient Derived Xenograft, PDX) on immunodeficient mice can meet this requirement. Patient-like tumor models are considered the most progressive because of their ability to maintain their initial properties, characterized by diversity at the histological and molecular level, after implantation. The aim of the study was to create a PDX model of human esophageal cancer in the cervical esophagus of immunodeficient mice.

Material and Methods. To create a PDX-model of human esophageal cancer, 11 male Balb/c Nude immunodeficient mice weighing 19-22 g were used. A tumor fragment was taken from a patient with a diagnosis of ulcerative cancer - a moderately differentiated squamous cell carcinoma without keratinization.

Results. As a result of implantation of a donor tumor fragment, complete engraftment of the material was observed in 6 (54.5 %) out of 11 animals, which is consistent with published data. according with the results of morphological studies, a patient-like xenograft is a squamous cell carcinoma, which histologically corresponds to the patient's tumor.

Purpose: to study gastrotoxic and ulcerogenic effects of a long-term administration of a newly synthesized compound from the hexaazaisowurzitan (thiowurtzine) series in rats, as well as to assess its effect on the transplantable tumor in mice.

Material and Methods. Lewis lung carcinoma was transplanted into mice, and thiowurtzine was prescribed for a long course together with cyclophosphamide. In the terminal stage of tumor development the mass of the primary node, the number and area of metastases in the lungs of mice were measured. Histological sections of the stomach were studied in rats after a 90-day administration of thiowurtzine.

Results. Thiowurtzine at therapeutic dosages of 50 and 100 mg/kg for a course of 19 days potentiated the effect of cyclophosphamide to inhibit tumor dissemination and exerted a direct antitumor effect in mice with lewis lung carcinoma. A dose of 1000 mg/kg for 90 days did not cause ulcerogenic action of thiowurtzine.

Conclusion. The absence of a stimulating effect on tumor growth in animal experiments and intactness in relation to the gastric mucosa during chronic administration of thiowurtzine allow us to recommend this innovative analgesic for clinical study as a concomitant analgesia in cancer patients.

Introduction. There are high-thech methods of nanoparticle production with controlled morphology and physical and chemical properties. Alumina-based mesoporous nanostructures have low toxicity and biocompatibility. FDI recommends alumina for biomedical application. Alumina inhibits the grow of cancer due to positive zeta-potential and low solubility in water. We observed the synergistic effect of joint application of doxorubicin and nanostructures. This approach reduces drug concentration and its toxicity.

Purpose: to synthesize nanostructures with different surface potentials and to study toxicity of these nanostructures alone and in combination with doxorubicin.

Material and Methods. The alumina-based nanostructures were obtained by the hydrolysis of nanopowder. The morphology of nanostructures was investigated by transmission electron microscopy with an integrated system of energy dispersive analysis. The phase composition of the particles was determined by x-ray diffraction. The effect of the synthesized nanostructures on the viability of cell lines was determined using the MTT test.

Results. The synthesized nanostructures have a low toxicity and can be used as an adjuvant for doxorubicin.

Conclusion. The combined use of doxorubicin and bicomponent nanostructures leads to an increase in the damaging effect of doxorubicin on Neuro-2a cells.

Introduction. surgical treatment of patients with pelvic bone tumors, in particular periacetabular tumors, remains challenging. There are many different reconstruction options after resection of these tumors. These include allo- and autografts, megaprosthesis, saddle endoprosthesis, custom-made endoprosthesis, 3D printing endoprosthesis, and femur transposition with the formation of neo-arthrosis. However, all of them are characterized by technical complexity and high risk of postoperative complications. There is still no standard procedure for reconstruction after resection of malignant periacetabular tumors. To date, modular endoprosthesis is a well-established reconstructive device in orthopaedic oncology to manage wide bone resections. Modular systems provide patient-specific endoprostheses that could be modified during surgery. In this article, we present the results of modular acetabular endoprostheses in the treatment of patients with periacetabular tumors.

Material and Methods. From 2011 to 2018, 30 patients underwent modular endoprosthetic reconstruction after periacetabular resection. There were 13 (43 %) male and 17 (57 %) female patients aged from 23 to 63 years (median age 45 years). Primary malignant bone tumors were detected in 19 (63 %) patients, giant cell tumor in 5 (17 %), local soft tissue sarcoma in 1 (3 %), solitary metastases of kidney cancer in 2 (7 %) and recurrent sarcoma after previous surgical treatment in 3 (10 %) patients.

Results. The average duration of surgery was 310 minutes (range: 145-520 minutes), blood loss was 5520 ml (range: 600-20000 ml). The median follow-up time was 36 months. Histological examination revealed a positive resection margin in 3 (10 %) patients. At a follow-up from 6 to 40 months, disease progression was detected in 10 (33 %) patients. Eight (27 %) patients died on disease progression. Complications of various types were diagnosed in 11 (37 %) patients. Infectious complications were the most common (30 % of patients). The average value of the functional assessment by the MSTS scale was 59 % (15-82%).

Conclusion. Modular endoprosthetic replacement for tumors of the acetabulum and hip joint is a promising surgical technique allowing adequate functional results to be achieved.

The purpose of the study was to assess results of Merzlikin-Paramonova's approach in liver surgeries.

Material and Methods. The topographical-anatomical and spatial relationships were studied on 20 corpses, taking into account assessment criteria according to A.Yu. Sozon-Yaroshevich. In clinical settings, Merzlikin-Paramonova's approach was applied in the treatment of 81 patients with hepatic diseases (cancer, hemangioma, alveococcosis), who underwent radical and palliative surgeries. Short-and long-term treatment outcomes during a 5 year follow-up were analyzed. Merzlikin-Paramonova's approach provided a sufficient overview of the liver, easy manipulation in the area of large bile ducts and blood vessels, as well as the ability to perform lymphodissection and combined operations.

Results. The Merzlikin-Paramonova's approach to liver surgeries has significant advantages over traditional surgical approaches, providing a good overview for revision of both primary and recurrent liver lesions. This surgical approach allowed the number of postoperative complications to be reduced due to less wound tension, rapid relief of pain and reduction in intra-abdominal hypertension, thus shortening the treatment time for patients. In the long-term postoperative period, the incidence of postoperative hernias decreased due to less damage to the nerve terminals of the anterior abdominal wall.

Conclusion. Merzlikin-Paramonova's approach is slightly traumatic due to innervation and muscle structure of the abdominal wall, is more physiological for the patient, and has a low rate of complications. This approach provides a good access to the organ requiring surgery and is able to perform radical cytoreductive surgeries. Merzlikin-Paramonova's approach to liver surgeries can be recommended for active implementation in clinical practice.

The review presents data on the role of ionizing radiation/hyperthermia as modulating factors in exosome secretion/composition. Tumor-derived exosomes are important participants in the formation of the tumor microenvironment. They modulate the inflammatory response in the tumor, influence the capability of fibroblasts and mesenchymal cells to differentiate into myofibroblasts, trigger the angiogenic process, promote epithelial to mesenchymal transformation of tumor cells and form the pre-metastatic nisches. The review describes the mechanisms of behavior of the recipient tumor cells receiving exosomes from irradiated cells, including activation of akt signaling, stabilization of MMP9/MMP2, and enhancement of exosome-mediated motility. In vitro models demonstrate the efficacy of exosomes from mesenchymal stem cells (MsC) to modulate both direct and abscopal effects of radiation therapy/hyperthermia. Exosomes derived from MsC are the most attractive carriers for the delivery of proteins, miRNAs, drugs, and metals to the recipient tumor cells. MsC-derived exosomes potentiate the efficacy of both radiotherapy and hyperthermia in vitro studies. However, some important aspects regarding a)             the most effective options for administering MsC/MsC exosomes to modulate radiotherapy/hyperthermia; b) radiation dose; c) options of hyperthermia; d) detailed mechanisms of the effect of irradiated MsC-derived exosomes on the tumor microenvironment and cancer cells, still remain poorly understood.

Background. Metabolic changes due to the progression of cancer and its aggressive treatment, lead to decreased food intake, related with development of cancer anorexia-cachexia syndrome (CACS) because of the complex interactions between pro-inflammatory cytokines and host metabolism. Beyond the physical and the metabolic consequences, cancer patients are often suffering from psychological distress, including depression.

Material and Methods. A literature search and analysis of data was conducted in PubMed and Medline databases since 2000 with the purpose to evaluate the effectiveness of additional oral methods of nutritional support for cancer patients.

Results. Nutritional support has a positive effect on response to cancer therapy and reduces the incidence of complications by optimizing the balance between energy expenditure and food consumption. In palliative care, nutritional support aims at improving patient’s quality of life by controlling symptoms such as nausea, vomiting and pain related to food intake.

Conclusion. The literature review confirms that nutritional intervention has a direct impact on quality of life and should be integrated into the global cancer care because of its significant contribution to QoL. Furthermore, monitoring and correction of nutritional status should be an integral part of the quality of life assesses with the aim to optimize its adequacy to the patient’s needs and expectations.

The purpose of the study was to analyze studies reporting pelvic floor reconstruction after extralevator abdominoperineal excision for rectal cancer, reconstruction options, including advantages and disadvantages.

Material and Methods. A literature search was performed using the Medline, Embase and Cochrane Library databases. Randomized clinical studies reporting the pelvic floor reconstruction after extralevator abdominoperineal excision of the rectum were evaluated.

Results. Although many surgical options are available for the management of perineal wounds after cylindrical abdominoperineal extirpation of the rectum, treatment remains challenging. Primary perineal defect closure is a simple and economical way to close a wound; however it has a high rate of perineal wound complications with occurrence of perineal hernia. Although various options of myo- and alloplastic reconstruction have several advantages, they are more labor-and cost-intensive.

Conclusion. There is a lack of randomized trials reporting the closure of the perineal defect after extralevator abdominoperineal extirpation of the rectum. There remains no consensus on which management strategy is superior; therefore, further studies are needed.

Background. Stomach cancer remains one of the most common malignancies worldwide, with high incidence rates and low rates of long-term treatment outcomes. Neoadjuvant therapy currently is increasingly being considered the standard therapy for locally advanced gastric and cardioesophageal cancers. A complete pathological response of the tumor has been reported to be observed in 8-20 % of patients. However, there is no guarantee that the evidence of pathological complete response will improve the cure results in all patients, and very little is known about prognostic factors after neoadjuvant therapy.

Case descriptions. Two clinical cases of locally advanced gastric cancer were described. The patients were treated with neoadjuvant chemoradiotherapy followed by D2 gastrectomy. Accelerated hyperfractionated radiotherapy (1 + 1.5 Gy/ day) to a total dose of 45 Gy at intervals of 4-5 hours was administered concurrently with chemotherapy (capecitabine: 1850 mg/m² orally twice daily at 12-hour interval; oxaliplatin: 85 mg/m² intravenously on days 1 and 21). Histological examination revealed complete histological regression of the primary tumor in two cases. However, in one of the cases, metastases in regional lymph nodes with grade 2 histological tumor regression were revealed. In the first case, the patient is still alive with no evidence of disease recurrence at over 6-years after treatment. In the second case, the patient died of the disease progression 3 years after treatment.

Conclusion. The data obtained are consistent with the few published studies reporting that pathological complete response to neoadjuvant therapy of not only the primary tumor but also regional lymph nodes is the key point determining the effectiveness of the combined modality treatment.

The purpose of the study was to demonstrate a rare clinical case of polyneoplasia associated with GIST, combining three malignant neoplasms of different nosological affiliation and different tissue origin. Scientific interest is caused by the need to study polyneoplasia associated with Gist, which can be explained by the concept of Rodriquenz M.G. et al. (2016), suggesting the special role of a solitary GisT in the potential development of polyneoplasia.

Material and Methods. The search for relevant sources was carried out in the Medline, Cochrane Library, Elibrary systems, includibg publications from January 2009 to October 2019. Of the 507 studies, 21 were used to write a systematic review.

Results. In the vast majority of cases, polyneoplasia is represented by two malignant neoplasms in a single patient. Primary multiple metachronous and primary multiple synchronous tumors with three or more tumors are observed very rarely. Among all multiple primary tumors, our attention was drawn to polyneoplasia containing GisT. A neoplasm associated with a GisT is localized mainly in the gastrointestinal tract, and also occurs in the organs of the urinary system, female genital system, thyroid gland, breast, lungs, and testicles.

Conclusion. This clinical case is a rather rare phenomenon of polyneoplasia associated with GisT of rectum, which combines three malignant neoplasms. It should be noted that primary Gist in the rectum occurs in 4% of cases.

Background. Solitary fibrous tumor (sFT) is a rare mesenchimal neoplasm of fibroblastic origin. There is no generally accepted classification for sFT. Surgery is the main treatment modality. Disease recurrence occurs in 2-14 % of patients. Re-surgery is recommended to treat recurrence because alternative treatment options are ineffective. Persistent hypoglycemia is observed in less than 5 % of patients, and values return to normal 24 days after tumor removal.

Case description. A 53-year-old woman was admitted to the Thoracic Department of PA. Gertsen Moscow Research Institute of Oncology with consciousness disorder at the level of spoor. The severity of the disease was caused by the syndrome of compression and displacement of the mediastinal structures to the left and respiratory failure: anemia, glycemia 1.2 pmol/ml. Immunohistochemical examination revealed solitary fibrous tumor with evidence of malignancy. In the preoperative period, to maintain the glycemia level within the normal range, continuous infusion of 10 % glucose solution was administered. The total infusion volume was 10 liters per day. Tumor in the right hemithorax was removed and atypical resection of the middle and lower lobes of the right lung was performed. In the postoperative period, glucose levels were in normal limits and additional treatment was not required.

Conclusion. SFT is a rare neoplasm of mesenchymal origin. The lack of clear diagnostic criteria and diagnostic standards for the description of individual cases remains relevant. Clinical manifestations of disease occur mainly in cases with large tumors. Early timely surgical excision of the tumor in case of suspicion of a solitary fibroid tumor is recommended, since over time, benign neoplasm may acquire a malignant behavior and metastasize.