Distinct Ezrin Truncations Differentiate Metastases in Sentinel Lymph Nodes from Unaffected Lymph Node Tissues,from Primary Breast Tumors,and from Healthy Glandular Breast Tissues

BACKGROUND: Lymph node metastasis status is a prognostic factor for further lymph node involvement and for patient survival in breast cancer patients. Frozen section analysis of lymph nodes is a reliable method for detection of macro-metastases. However, this method is far less effective in detecting micro-metastases, requesting improved diagnostic procedures. METHODS: We investigated expression and truncation of ezrin in (i) sentinel lymph node metastases, (ii) unaffected axillary lymph nodes, (iii) primary breast tumors, and (iv) healthy glandular breast tissues using 2D gel electrophoresis, SDS-PAGE, and mass spectrometry in addition to Western blotting. RESULTS: Full-length ezrin (E1; amino acids 1–586) is present in all four investigated tissues. Two truncated ezrin forms, one missing about the first hundred amino acids (E2a) and the other lacking about 150 C-terminal amino acids (E2b) were detectable in primary tumor tissues and in sentinel lymph node metastases but not in glandular tissues. Strikingly, an ezrin truncation (E3) which consists approximately of amino acids 238–586 was found strongly expressed in all sentinel lymph node metastases. Moreover, an N-terminal ezrin fragment (E4) that consists approximately of amino acids 1–273 was identified in sentinel lymph node metastases as well. CONCLUSIONS: We show for the first time the existence of tissue-dependent specific ezrin truncations. The distinguished strong Western blot staining of ezrin E3 in sentinel lymph node metastases underlines its capability to substantiate the occurrence of lymph node (micro)metastases in breast cancer patients.     

胃癌淋巴结微转移的临床研究进展

胃癌是我国目前最常见的恶性肿瘤之一,微转移是恶性肿瘤在发展过程中所形成的尚处于临床不可探测阶段的微小转移灶,播散并存活于淋巴系统、血液循环、骨髓、肝、肺等组织器官中,是恶性肿瘤复发和转移的根源。目前对胃癌淋巴结微转移的深入研究主要集中在通过寻找不同的检测方法、途径和特异性肿瘤标志物,对常规检查淋巴结为阴性的胃癌,微转移检测可能对准确地确定临床分期、指导治疗、判断预后有积极临床意义。现就胃癌微转移检测研究的现状和存在的问题予以综述。     

Lymph node metastases of papillary thyroid cancer in immunohistochemical and molecular examination--preliminary report

BACKGROUND: Total thyroidectomy with lymphadenectomy is the most typical operation in a case of papillary thyroid cancer. Range of lymph node resection still remains a matter of controversy. In some publications treatment of lymph node metastases doesn't affect survival, so only selective lymph node resection is the extended enough operation. The others remark that, local relapse- the worst prognostic factor, appears the most often in the lymph nodes, so they suggest more aggressive treatment. To solve that problem we try to find more sensitive methods to examine lymph nodes. AIM: To compare the results of detection lymph node metastases of papillary thyroid cancer by immunohistochemistry with the results of RT- PCR for thyroglobulin (Tg) mRNA. MATERIAL AND METHODS: Each of one hundred eighty four cervical lymph nodes obtained from 24 patients, operated in our Department was divided into 2 halves: one was used for conventional histopathology and immunohistochemistry, the other part was investigated by RT- PCR for Tg mRNA. Immunohistochemical staining for Tg was performed on formalin-fixed, paraffin-embedded sections with anti-Tg antibodies. RESULTS: According to routine, histopathological examination 8 (33.5%) patients had involved lymph nodes. One hundred correspondence of the results of immunohistochemistry and histopathology was observed. We obtained different results of examination of the lymph nodes in 6 (25%) patients. In four patients (16.7%) RT-PCR was more sensitive in detection of positive lymph nodes, in two patients (8.3%) it revealed less metastasized lymph nodes than immunohistochemistry. The remaining 18 patients didn't have any differences, fourteen (58.3%) of them had the negative lymph nodes and four (16.7%) had positive, the same lymph nodes in all examinations. Finally, according to RT-PCR 10 (41.7%) of the patients had metastasized lymph nodes. COCLUSION: Tg RT-PCR is a sensitive method of detection of papillary thyroid cancer cells and may help to detect the metastases of papillary thyroid cancer in regional lymph nodes.     

Histoenzymological and ultrastructural changes of axillary lymph nodes with breast cancer metastases

Histoenzymatic and ultrastructural changes were studied in axillary lymph nodes from patients with breast cancer by comparison between lymph nodes without metastases, with incipient metastases and completely metastatically transformed. Metastases is preceded by intense macrophagic reactions of lymph nodes, and prepared by the development of vascular stroma. Neoplastic cells in course of invasion presented an intense respiratory activity, while those replacing the lymphoid elements an accentuated synthesis of glycoproteins.     

超声弹性成像技术对腋窝淋巴结性质的诊断价值

目的:研究超声成像技术对腋窝淋巴结性质的诊断价值。方法:从2013年5月至2014年2月,选择我院50例乳腺癌患者,对所有患者进行弹性成像技术检测出74个腋窝淋巴结。对所有腋窝淋巴结使用四分法进行评分,将其与手术病理结果进行比较。结果:74个腋窝淋巴结中,反应性淋巴结有42个,纵径为(0.9-2.4)cm,平均纵径为(1.31±0.33)cm;乳腺癌腋窝淋巴结转移个数为25个,纵径为(1.2±3.8)cm,平均纵径为(2.04±0.72)cm。良性淋巴结弹性评分大多为1分(54.55%)以及2分(27.27%),恶性淋巴结评分多为3分(63.33%)以及4分(20.00%)。恶性淋巴结评分为(3.12±0.61)分,良性淋巴结评分为(1.68±0.74)分,结果显示,两组淋巴结弹性评分具有较大差异(即P<0.05),具有可比性。结论:综上所述,超声弹性成像技术操作较为简便,效果较为直观,评分法能够提供组织的硬度信息,在临床工作中,与常规超声联合应用有利于提高评价腋窝淋巴结良恶性性质的准确度。值得临床推荐使用。     

Comparative morphometric analysis of thyrocytes in a primary tumor and regional metastases in papillary thyroid gland cancer

OBJECTIVE: To perform a comparative analysis of thyrocyte nuclei and the aggregability degree in tumor cells in the thyroid gland with papillary cancer and in cervical lymph nodes with metastases. STUDY DESIGN: Thyrocytes in papillary cancer and those of cervical lymph nodes with its metastasis have been studied with the help of morphometry. RESULTS: As a result of mathematical transformation of the initial morphometric database, quantitative features of thyrocyte nuclei and aggregates characterizing the norm, papillary cancer and regional metastases were obtained. These features were united into 2 systems of decision criteria on the base of a set of quantitative features of thyrocyte nuclei and aggregates. Analysis was performed among the groups of comparison with the help of these systems. CONCLUSION: Malignant cells of the primary tumor have been shown to have evident quantitative features of nuclear atypia and a higher degree of aggregability compared with the norm. The differences between the quantitative features of nuclei and aggregates in malignant cells of the primary tumor in the thyroid gland and its metastases in cervical lymph nodes were less pronounced.     

Confirmation of histology of PET positive lymph nodes recovered by hand-video-assisted thoracoscopy surgery

PET/CT (Positron Emission Tomography-Computed Tomography) is an advanced diagnostic imaging device that combines both PET and an X-ray CT. This study evaluates the effects of PET/CT on detecting primary tumors and metastases, and looks at the therapeutic effect of minimally invasive surgery on esophageal cancer patients. Eighty patients with esophageal cancer were enrolled in the study between January, 2004 and December, 2007, who were randomly divided into two groups of 40, one of which was treated with hand-video-assisted thoracoscopy surgery (HVATS) esophagectomy and one of which was treated with conventional surgery. All patients underwent a PET/CT scan 2-3weeks before their operation, and their cervical, thoracic and upper abdominal lymph nodes were biopsied. All the primary esophageal lesions showed high FDG uptake. The maximum standardized uptake value (SUV) was 3.78-25.64 (11.73±5.32), while the mean SUV was 3.65=16.92 (9.12±4.37). Using 2.5 as the SUV standard, all esophageal lesions were detected by PET/CT image. Of the 80 patients, 53 had lymph nodal metastases, with a total of 142 metastatic lymph nodes, which showed high FDG uptake. The maximum SUV was 2.77-14.63 (7.98±3.25), and the mean SUV was 2.31-12.84 (5.34±3.19). The visual analysis from the PET/CT scan showed a sensitivity of 86.62%, a specificity of 95.85%, a positive predictive value of 93.89%, a negative predictive value of 90.69% and an accuracy of 91.94%. The PET/CT scan showed a high sensitivity and specificity in detecting primary esophageal cancer and lymph nodal metastases. The mean post-surgery life expectancies for patients undergoing HVATS and conventional surgery are 27.93months and 28.05months, respectively. The two groups showed no statistically significant difference. We thus conclude that PET/CT combined with HVATS is a new choice for esophageal carcinoma patients.     

A specific vaccine effective against stage I and stage II malignant disease in guinea pigs effect of variations in preparations and storage

Summary Guinea pigs, each with an established, syngeneic dermal line 10 tumor and lymph node metastases, were immunized by intradermal injection of a mixture of irradiated line 10 cells and an emulsion containing heat-killed BCG. Immunization eradicated 7- or 10-day-old dermal tumors (about 10 or 12 mm in diameter, respectively) and prevented growth of microscopic lymph node metastases. Fourteen-day-old dermal tumors (about 15 mm in diameter) were not rejected by immunization.Guinea pigs with stage II disease (21-day-old dermal tumors and palpable metastases in the first draining lymph node) were treated by excision of the dermal tumor and the first draining lymph node, and by specific immunization. This treatment eliminated tumor cells remaining in the second draining lymph nodes. The surgical treatment alone was not curative, palpable metastases in the second draining lymph nodes progressed and the animals died (some with visible lung metastases).Emulsions containing killed BCG were good adjuvants even after prolonged storage at 4° C, but lost most of their adjuvant activity after autoclaving or freezing.     

Completion total thyroidectomy in children with differentiated thyroid cancer

INTRODUCTION: The optimal surgical treatment of children with differentiated thyroid cancer remains an important point of discussion. Especially the need for completion operation is questioned in young patients. Our objective was to examine the rate of residual neoplastic disease after non radical initial operation. MATERIAL AND METHODS: From the 235 children diagnosed with differentiated thyroid cancer, 131 (56%) needed completion operation due to incomplete primary surgery. Completion operation involved thyroid bed, lymph nodes or both respectively in 91 (39%), 13 (6%) and 27 (11%) cases. Risk factors responsible for residual disease were evaluated by means of logistic regression analysis. RESULTS: Residual disease was detected in 46 (35%) of reoperated children (25% in thyroid bed and 85% in lymph node of lateral neck compartment). Sex and age did not influence the risk of residual disease in thyroid bed or lymph nodes. Papillary type of cancer and multifocality increased risk of residual disease in thyroid bed respectively by the factor of 15 (95% CI: 2-125) and 2.3 (95% CI: 1.2-4.4). Infiltration of thyroid capsule did not correlate with the risk of residual disease. Lymph node metastases in primary operation increased risk of residual disease by the factor of 16 (95% CI: 1.2-245). Histopathology, multifocality of primary tumour or infiltration of lymph node capsule did not influence the risk of residual disease in lymph nodes of lateral neck compartment. CONCLUSIONS: In children with differentiated thyroid cancer residual disease is diagnosed in about 1/3 of non radically operated cases. This high incidence justifies completion operations. The risk of residual disease is significantly increased in papillary thyroid cancer, multifocal tumours and cases with lymph node metastases.     

Recurrent ovarian cancer presenting as an isolated right supraclavicular lymph node metastasis: a case report

ABSTRACT: INTRODUCTION: The majority of ovarian cancer recurrences are in the abdomen. However, some cases relapseas isolated lymph node metastases, mostly in pelvic or para-aortic nodes. Peripheral isolatedlymph node metastasis is rare. CASE PRESENTATION: A 69-year-old Japanese woman had recurrent ovarian cancer presenting with isolated rightsupraclavicular lymph node metastasis. After surgical resection and combinationchemotherapy with carboplatin and paclitaxel, her right supraclavicular lymph nodecompletely regressed. CONCLUSIONS: Isolated peripheral lymph node metastasis, including the right supraclavicular lymph node,can occur without a macroscopic abdominal lesion. Clinicians should carefully examineperipheral lymph nodes for recurrence.     

Tumour-induced immune modulation of sentinel lymph nodes

Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.     

磁共振靶向对比剂在淋巴结成像中的研究进展

准确评价淋巴结转移与否关系到对肿瘤患者的分期和预后的判断。目前对淋巴结良恶性诊断的主要依据为淋巴结的大小和形态,正常大小的转移性淋巴结很可能被遗漏,增大的淋巴结是良性增生还是恶性转移也很难鉴别。近年来随着MR特异性对比剂,特别是MR靶向淋巴结对比剂的发展,MR淋巴成像（MR Lymphography,MRL）显示了极为诱人的前景。该文主要介绍MR淋巴靶向对比剂的研究进展。     

Further characterization of a clinically relevant model of melanoma metastasis and an effective vaccine

A major problem in evaluating the effectiveness of tumor cell vaccination and other biological therapies is the variability of experimental models. In this study we have further developed and characterized a model for metastatic melanoma that approximates the major clinical stages of metastatic dissemination: stage I-growth of the primary (local) tumor, stage II-dissemination to regional lymph nodes, and stage III-metastasis to distant organs (lungs). C57BL/6 mice were challenged subcutaneously with B16 F10 murine melanoma cells in the midtail, and within 3 weeks 100% of the mice had local tumors growing in their tails. By 5–7 weeks after challenge, most of the mice had developed metastases to the inguinal lymph nodes and subsequently had metastatic colonies in the lungs and in the bone marrow. Preimmunization of mice with a formalinized extracellular antigen vaccine, derived from B16F10 melanoma cells, provided partial inhibition of the growth of the primary melanoma tumors, as well as reducing the number of metastases to the regional (inguinal) lymph nodes and lungs along with concomitantly increasing survival time. This model for melanoma metastasis provides a reasonable and reproducible test system for the study of anti-melanoma immunity and the different cellular and humoral mechanisms involved.This work was supported in part by National Institutes of Health grants R37 CA45148 and R30 CA13943     

Adjacent thoracic lymph node metastases originating from two separate primary cancers: case report

Reported is an unusual case of adjacent thoracic lymph nodes demonstrating metastases from two different primary malignancies. A 51 year-old woman with a previous history of bilateral breast cancer underwent a radical gastro-oesophagectomy for adenocarcinoma of the lower third of the oesophagus. The resection specimen demonstrated breast and oesophageal metastases in adjacent thoracic lymph nodes. Mechanisms for this phenomenon, including the known local immune suppression on lymphoid cells by oesophageal carcinoma cells, are discussed.     

Cervical lymph node metastases of thyroid carcinoma - an alternative of the "lateral aberrant thyroid"

The neoplastic thyroid tissue found in the laterocervical lymph nodes of euthyroid patients is associated with an intrathyroid carcinoma identified in the subsequently operated gland, asserting its metastic origin. Eighty percent of the thyroid carcinomas present cervical metastases in a variable number of lymph nodes belonging to more than one topographic group.     

Anatomo-topographic features of the deep lymph nodes of the neck in adult humans]

Profounod cervical lymph nodes were studied on 35 corpses and 30 complexes of organs of the head and neck in adult man by method of dissection after a preliminary injecting the lymphatic vessels and nodes. Under study were the lymph nodes of the anterior part (prelaryngeal, prethyroid, pretracheal and paratracheal groups) which are disposed under the pretracheal lamina of the cervical fascia. The lymph nodes of the lateral area of the neck are concentrated along the internal jugular vein, accessory nerve and the transversal artery of the neck. The lymph nodes disposed along the internal jugular vein are divided into 3 groups: superior, medial and inferior. The lymph nodes disposed in the lateral area of the neck are of different types. The obtained data can be used for decoding data of lymphography.     

The reliability and accuracy of intraoperative imprint cytology of sentinel lymph nodes in breast cancer

OBJECTIVE: Sentinel lymph node (SLN) biopsy is a new component of the surgical treatment of breast cancer that accurately predicts axillary status. In this study the authors evaluated the accuracy of intraoperative imprint cytology (IC) in comparison with definitive histologic evaluation of SLN in breast cancer patients. METHODS: A total 413 women with breast carcinoma and clinically negative axillary nodes underwent breast surgery and SLN biopsy. Mapping of SLN involved injection of (99m)Technecium labelled human albumin nanocolloid particles and Patent Blue dye. At the Department of Pathology, SLNs were bisected along its major axis. Both halves were imprinted 2-4 times on the slides and immediate staining with Hemacolor (Merck Germany) was performed for intraoperative examination. Imprint node negative women underwent no further surgery, while node positive women proceeded to full axillary clearance. Histological analysis of the SLN involved serial sectioning of the whole node with H&E and immunostaining for cytokeratin. RESULTS: Definitive histology revealed metastases (pN+) in 159/413 patients (38.5%): 69 (16.7%) macro metastases, 57 (13.8%) micro metastases, and 33 (8%) women with only isolated IHC positive cells or positive cell groups smaller than 0.2 mm (pNO sn+). The other 254 women had negative SLN biopsy. Imprint cytology detected 54/69 macro metastases, and 4/57 micro metastases. In the group with negative SLN (254), 2 cases were 'false positives'. CONCLUSIONS: Imprint of SLN biopsy can identify a negative axilla with high accuracy (specificity 99.2%). Overall sensitivity is only 36.5%, but macrometastases are detected in 77% which is important for performing ALDN in one session with operation of primary tumour.     

Tumor lymphangiogenesis and melanoma metastasis

Malignant melanomas of the skin primarily metastasize to lymph nodes, and the detection of sentinel lymph node metastases serves as an important prognostic parameter. There is now compelling evidence that melanomas can induce lymphangiogenesis (growth of lymphatic vessels), mainly at the tumor-stroma interface, and that the level of tumor lymphangiogenesis is correlated with the incidence of sentinel lymph node metastases and with disease-free survival. Thus, tumor lymphangiogenesis can serve as a novel prognostic predictor in melanoma. Vascular endothelial growth factor (VEGF)-C, released by melanoma cells and by tumor-associated macrophages, likely represents the major lymphangiogenic factor in melanoma, although other members of the VEGF family might also be involved. The recent discovery that tumors can induce a premetastatic niche, by inducing lymphatic vessel growth in sentinel lymph nodes even before metastasis, and that lymph node lymphangiogenesis enhances metastatic spread, indicates that activated lymphatic vessels represent novel targets for the detection and/or therapy of melanoma metastases.     

Carcinoid tumor of the kidney: case report and review of the literature

Carcinoid tumors are low-grade malignant tumors that arise from neuroendocrine cells. Primary renal carcinoid tumors are extremely uncommon. They seem to be more indolent than renal cell carcinomas, although metastases to regional lymph nodes, liver, and bone have been described. The presence of metastases seems to indicate a more malignant course; however, even with metastases a patient might live for 3 or 4 years. Renal carcinoid tumors should be managed by radical or partial nephrectomy, and good outcomes have been obtained for organ-confined disease after radical excision. Conventional methods of imaging are inadequate for detecting smaller carcinoids, so somatostatin receptor scintigraphy should complement computed tomography and magnetic resonance imaging when searching for occult or metastatic disease. Close follow-up after surgery is necessary.     

Collateral presentation of antigens as physiological prototype for lymph node metastases

The formation of lymphogenic metastases remains enigmatic. In particular, the much more pronounced predilection of carcinomas than of sarcomas to metastasizing into regional lymph nodes is an unsolved problem. We suggest that this difference could be due to the ability of epitheliocytes for a hypothetical process termed by us “collateral presentation of antigens”. Under conditions of infection of epithelium with intracellular pathogens or during inflammation, epithelial cells acquire a special receptor phenotype, undergo the epithelial-mesenchymal transition, and migrate along lymphatic vessels into lymph nodes where they present antigen to immunocytes. The collateral presentation of antigens can be of significant biological importance in the case of insufficient classical pathway of antigen presentation (by dendritic cells) or on disturbance in the death mechanisms of the infected cells. Depending on conditions of induction of the epithelial-mesenchymal transition and on possible ability of epitheliocytes to express MHC II with co-stimulating molecules, two pathways, “container-mediated” and “MHC II-dependent”, of antigen presentation in lymph nodes resulting in development of immunogenesis or anergy of immunocytes are supposed to exist. All pathways of delivery of the epithelial cells into lymph nodes and of antigen presentation by epitheliocytes terminate by death of these cells. The lymphogenic metastasizing realizes the same mechanism under conditions of tumor disease; however, this is not associated with cell death, but they actively colonize the lymph node. The proposed hypothesis allows us to explain the metastasizing of sarcomas into lymph nodes. The main prerequisite for lymphogenic metastasizing seems to be related with the mesenchymal-epithelial transition of sarcoma cells promoting their involvement in the presentation of antigens.