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Dr. Marina Senchukova ,

7th Global Summit on Cancer therapy. The Cavitary ” Type of Angiogenesis in Gastric and Breast Cancer. Clinical and Morphological Aspects. Dr. Marina Senchukova , Associate Professor, Department of Oncology, Orenburg State Medical Academy, Russia.

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Dr. Marina Senchukova ,

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  1. 7th Global Summit on Cancer therapy The Cavitary” Type of Angiogenesis in Gastric and Breast Cancer. Clinical and Morphological Aspects Dr. Marina Senchukova, Associate Professor, Department of Oncology, Orenburg State Medical Academy, Russia

  2. At 1971 year J. Folkman formulated his celebrated scientific concept that the tumor growth and metastasis depend on angiogenesis and lymphangiogenesis triggered by chemical signals from tumor cells. An angiogenesis activity correlated with the depth of tumor invasion, the presence of metastases in regional lymph nodes (RLN) and the prognosis of the disease (Ding S. et al, 2006; Ma J. et al, 2007; Lazar D. et al, 2008; Poon RT et al, 2003; Wang YD et al, 2007). The tumor vessels are heterogeneous in origin, morphologyas well as in the clinical significance and in their sensitivity to the anti-angiogenic therapy (Dvorak et al, 1995; Nagy et al, 2012).

  3. The “cavitary” type of angiogenesis I step - The formation of “cavitary” structures in tumor stroma or the adjacent gastric mucosa; II step - their lining by endothelial cells; III step - their merger into the blood vessels of the organ. * Senchukova, M. & Kiselevsky, M.V. (2014). The “Cavitary” type of angiogenesis by gastric cancer. Morphological characteristics and prognostic value, J Cancer, 5 (5), 311 – 319. * Senchukova M, Ryabov A, Karmakova T, Tomchuk O, Stadnikov A (2015) The Morphological Features of “Cavitary” Type Angiogenesis in Diffuse and Intestinal Types of Gastric Cancer and Its Relationship with Tumor-Infiltrating Immune Cells. BJMMR 7(4): 272-284. *Senchukova M, Nikitenko N, Tomchuk O, Zaitsev N, Stadnikov A. (2015). Different Types of Tumor Vessels in Breast Cancer. Morphology and Clinical Value. Springer plus 4; 512.

  4. Characteristics of the patientswith gastric cancer 73 patients with gastric cancer The average age was 61.2±9,3 years (from 34 to 78 years) The median – 61 years. 59 patients with T1-T2 stages of ductal invasive carcinomas. The average age was 58,1±10.1 years (from 35 to 75 years). The median – 57 years. The patients with decompensation of chronic diseases, acute infection pathology, severe allergic processes were not included in the study as well as the ones who received corticosteroids, antihistamines, non-steroidal anti-inflammatory drugs and neoadjuvant chemotherapyradiotherapy.

  5. Clinicopathologic characteristics of gastric carcinoma cases Clinicopathologic variables Number of cases (n) Percent (%) ______________________________________________________________________ Gender Male 43 58.9 Female 30 41.1 Location of tumor Upper third 14 19.2 Middle third 18 24.7 Lower third 39 53.4 Total cancer 2 2.7 Lauren classification Intestinal type 41 56.2 Diffuse type 32 43.8 Differentiation Well (G1) 27 36.9 Moderate (G2) 14 19.3 Poorly (G3-G4) 9 12.3 Signet ring cell carcinoma 23 31.5 Nodal status (N) pN0 43 59.9 pN1 9 12.3 pN2 21 28.8 Tumor status (T) pT1 16 21.9 pT2 18 24.7 pT3 36 49.3 pT4 3 4.1 Stage (TNM) T1-2N0M0 34 46.6 T3N0M0 9 12.3 T3-4N1M0 9 12.3 T3-4N2M0 21 28.8

  6. Surgery • Subtotal distal resection – 56 patients (76.7%) • Subtotal proximal resection – 10 patients (13.7%) • Gastrectomy – 7 patients (9.5%) • D2 lymphadenectomy - all patients • With D3 elements – 38 patients (52.0%).

  7. Clinicopathologic characteristics of breast carcinoma cases Clinicopathologic variables Number of cases (n) Percent (%) _________________________________________________________________________________ Age <50 11 18.6 >50 48 81.4 Tumor status (T) pT1 21 35.6 pT2 38 64.4 Nodal status (N) pN0 30 50.8 pN1 15 25.4 pN2 1 1.7 pN3 13 22.1 Number of lymph nodes 0 30 50.8 1-3 20 33.9 4-6 6 10.2 >6 3 5.1 Tumour grade G1 7 11.9 G2 42 71.2 G3 10 16.9 ER status Negative 29 49.1 Positive 30 50. PR status Negative 38 64.4 Positive 21 35.6 HER2/neu status Negative 48 81.4 Positive 11 18.6

  8. Surgery Modified radical mastectomy - 45 patients (76,2%) Breast-conserving surgery – 14 patients (23,8%), all with adequate lymph node dissection (at least 10 - 12 nodes were examined).

  9. METHODS The specimens of gastric mucosa and tumor were stained with Mayer’s hematoxylin and eosin and by van Gieson. We used the follow antibodies for IGH: • anti-CD4; • anti-CD-8; • anti-CD20; • anti-CD68; • anti-CD34 The visualization system has included DAB and Hematoxylin counterstaining. For negative control sections, primary antibody was replaced with phosphate-buffered saline and processed in the same manner.

  10. METHODS It was evaluated: • The number of “cavitary” structures type-1 and atypical dilated vessels. These vessels were estimated by the visual analog way using x100 magnification (none, single – no more than two in the field of view, and multiple – more than two in the field of view). • The presence of“cavitary” structures type-2 • The density of CD4, CD8, CD20 lymphocytes and CD68 macrophages (on the relative area unit equal to 0.42 x 0.28 mm²). • Microvessels density was assessed using antibodies to CD34, in accordance with the international consensus on the methodology and criteria for quantitative evaluation of angiogenesis in human solid tumors [Vermeulen PB]. • The severity of polymorphonuclear cell infiltration (PCI) was calculated as density of cells on area unit equal to 0.42 x 0.28 mm²; The obtained data were compared with the clinical and morphological characteristics of gastric and breast cancer.

  11. Statistical methods • Spearman’s rank correlation or gamma correlation (for the evaluation of the correlations between different data); • Chi-squaretest(it wascarriedouttoanalyzethedifferenceofdistributionamongthecategorizeddata). • The survival was analyzed by the Kaplan-Meier method. • Log-rank test (it was used to compare survival curves between subgroups of patients). • Cox'sproportional hazards model (it was used for multivariate analysis of prognostic factors). • Odds ratio (OR) and a 95% confidence interval (CI) (this methods were used for the estimated the association between the 3-year survival and different types of vessels). A value of P< 0.05 was considered statistically significant.

  12. The “cavitary” type of angiogenesis I step - The formation of “cavitary” structures in tumor stroma or the adjacent gastric mucosa; II step - their lining by endothelial cells; III step - their merger into the blood vessels of the organ.

  13. There are two main types of the formation of the “cavitary” structures. The first type is associated with the abruption of layers of epithelial cells from their underlying foundation and their desquamation into the lumen of the “obliterated” cancerous glands.

  14. The first type of “cavitary” structures (CS type-1) formation The abruption of tumor cells from their underlying foundation and their desquamation into the lumen of the cancerous glands in breast (A) and gastric (B) cancer. This step of angiogenesis corresponds to the previously described the “Retraction Artifact” (Acs G et al, 2007; Acs G et al 2012). A - H&E stain (x400); B - H&E stain (x100)

  15. The main sign of “cavitary” angiogenesis of type-1 is the presence of CS with partial endothelial lining. The cytoplasm of cells lining of the CS type-1 has an uneven surface with a number of protuberances CS type-1 with partial endothelial lining (black arrows); CS type-1 without endothelial lining (green arrows); Blood vessel with tumor emboli in the lumen (red arrow); Staining with CD34 antibodies, x400.

  16. The features of “cavitary” angiogenesis of type-1 in gastric and breast cancer CS type-1 without endothelial lining (black arrows); CS type-1 with partial endothelial lining (green arrows); Dilated vessel with tumor emboli in the lumen (red arrow); Staining with CD34 antibodies, Fig A – samples of gastric cancer, x100; Fig B – samples of breast cancer, x400.

  17. The features of “cavitary” angiogenesis of type-1 in gastric and breast cancer Fig. A shows the dilated blood vessels with tumor emboli in the lumen in the samples of gastric cancer, x400; Fig. B shows the atypical dilated vessel with the marked atypia of the lining endothelial cells in the samples of breast cancer, x 400; Staining with CD34 antibodies.

  18. The features of atypical dilated vessels in breast cancer Atypical dilated vessel (red arrows): Fig. A - with tumor emboli in the lumen; Fig. B – with free (unrelated with wall of vessel CD34 positive cellsand tumor emboli in the lumen, CS type-1 without endothelial lining (black arrows); Staining with CD34 antibodies, x 400.

  19. The second type of “cavitary” angiogenesis in gastric cancer. This type angiogenesis are associated with a characteristic structure of tumor stroma presented by loose fine-fibered connective tissue with a distinctive cellular structure (CS type-2). Fig. A shows a characteristic cellular structure (CS type-2) of the connective tissue in the stroma bordering upon the tumor tissue; Fig. B shows the CS type-2 (red arrows) and cavitary vessels type-2 (black arrows). H&E stain, x400.

  20. The second type of “cavitary” angiogenesis in breast cancer Fig. A - B show a characteristic cellular structure and CS type-2 in the peritumoralstroma, H&E stain, x400.

  21. The “cavitary” vessels type-2 with endothelial liningin gastric and breast cancer Fig. A shows the CS type-2 in gastric cancer; Fig. B shows the CS type-2 in breast caner, Staining with CD34 antibodies, x 400. A

  22. The clinical significance of “cavitary” type of angiogenesis on the examples of gastric and breast cancer

  23. THE “CAVITARY” STRUCTURES TYPE-1 IN GASTRIC CANCER The presence of “cavitary” structures type-1 in tumor stroma correlated with: the tumor sizes (ρ=0,316, p=0,006); histological type (gamma=0,344, p=0,01); Grade (gamma=0,318, p=0,005); Tumor Stage (gamma=0,549, p<0,00001); Nodal Stage (gamma=0,520, p=0,00003); 3-year overall survival rate (gamma=-0,778, p<0,00001) 3-year Relapse-free survival rate (gamma=-0,766, p<0,00001).

  24. The tumor sizes according to the number of “cavitary” structures type-1 in tumor stroma Median test (p=0,02)

  25. The frequency of CS type-1 depending on the histology type of gastric cancer X2=3,42, p=0,18

  26. The frequency of CS type-1 depending on the Grade of gastric cancer X2=9,64, p=0,14

  27. The frequency of CS type-1 depending on the Tumor Stage (T) of gastric cancer X2=17,48, p=0,008

  28. The frequency of CS type-1 depending on the Nodal Stage (N) of gastric cancer X2=11,69, p=0,01

  29. Survival of the patients depending on the number of “cavitary” structures type-1 A B A - The curves of 3-year relapse-free surviving (p=0,00001, Log-Rank Test) B - The curves of 3-year overall surviving (p=0,0012, Log-Rank Test )

  30. With or without the multiple “cavitary” structures type-1, the 3-year overall survival was 52.7% and 93.9%respectively (p=0,0013, OR=15,0, 95% CI=2,96 – 76,31), and relapse-free survival - 32.4% and 87.7% respectively (t=0,0001, OR=14,93, 95%CI=4,34-51,38). • The multivariate Cox proportional hazard regression analysis indicated that TNM stage (p=0,003), nodal stage (p=0,013), the number of “cavitary” structures type-1 (p=0,005) were significantly independent prognostic factors in patients with GC. 

  31. THE “CAVITARY” STRUCTURES TYPE-1 IN BREAST CANCER The presence of “cavitary” structures type-1 with partial endothelial lining correlated with: the number of atypical dilated cappilaries(gamma=0,753, p<0,00001); ER status (gamma=-0,493, p=0,004); PR status (gamma=-0,627, p=0,001); the presence of tumor emboli in the vessels (gamma=0,515, p=0,004); the presence of free CD34 positive cells in the lumen of tumor vessels (gamma=0,673, p=0,001). :

  32. THE FREQUENCY OF CS TYPE-1 DEPENDING ON THE NUMBER OF ATYPICAL DILATED VESSELS X2=19,73, p=0,0006

  33. THE FREQUENCY OF CS TYPE-1 DEPENDING ON THE ESTROGEN RECEPTOR STATUS X2=4,66, p=0,03

  34. THE FREQUENCY OF CS TYPE-1 DEPENDING ON THE PROGESTERONE RECEPTOR STATUS X2=11,69, p=0,01

  35. THE NUMBER OF CS TYPE-1 DEPENDING ON THE PRESENCE OF LYMPHOVASCULAR INVASION X2=2,01, p=0,16

  36. THE CAVITARY STRUCTURES TYPE-2 IN GASTRIC CANCER In gastric cancer the presence of “cavitary” structures type-2 correlated only with the histological type of tumor (gamma=0,403, p=0,008). By the diffuse and intestinal type of GC they were revealed in 55,9% and 35,0% cases respectively (р=0,07).

  37. THE CAVITARY STRUCTURES TYPE-2 IN BREAST CANCER The number of CS type-2 correlated with: Her2/new status (gamma=0,680, p=0,0002) the presence of lymphovascular invasion (gamma=-0,441, p=0,01). The CS type-2 were observed in 100,0% and 56,3% cases in the positive and negative Her2/new status (χ2=9,69, р=0,008). The tumor emboli in vessels were revealed in 43,7%, 69,2% and 75,0% cases in the absence of CS type-2, single and multiple ones (χ2=3,71, р=0,16).

  38. The density of CD68 macrophages in gastric mucosa according to the number of “cavitary” vessels type-1 Kruskal-Wallis ANOVA by Ranks, p=0,057

  39. The density of CD20 B-lymphocytes in tumorstroma according to the presence of CS type-2 Mann-Whitney U Test, p=0,035

  40. The presence of CS type-2 according to the presence of focal CD20-cell infiltrates at the boundary of gastric mucosa and tumor X2=10,64, p=0,001

  41. Factors that may be associated with “cavitary” angiogenesis type-1 • The disorder of the adhesive properties of tumour cells; • The inflammatory changes in the tumour stroma and the adjacent GM. The formation of “cavitary” structures type-1 and type-2 is likely related to the different classes of tumor-infiltrating immune cells (type-1 – with CD68 macrophages, type-2 – with CD20 B-lymphocytes; • The focal disruptions in the tumor capsule associated with increased immune cell infiltration (Man Y.G., 2010; Man Y.G. et al, 2013). • The increase the vascular permeability that may influence the process of stroma “retraction” and promote the formation of a fibrin matrix and a migration of endothelial cells (Nagy J.A. et al, 2012).

  42. Thank for your attention

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