Appearance Of Lymph Node Metastases Research Articles

A vocal cord palsy caused by the uterine cancer metastatic tumor in the mediastinum revealed in a patient with a thyroid lesion: a case report and review of the literature

BackgroundThe main cause of vocal cord palsy (VCP) is idiopathic impairment of the recurrent laryngeal nerve (RLN). However, solid tumors along the pathway of the RLN can also impact the nerve’s function. We presented a patient with a thyroid lesion and VCP due to a bulky metastatic mass (uterine cancer) on the aortic arch field in the mediastinum. The report aims to show the significance of comorbid tumors in thyroid pathology and the importance of additional diagnostic methods in avoiding unnecessary surgeries. A patient’s lifetime and the outcome of the disease were also presented.Case presentationA 58-year-old Ukrainian woman with a hoarse voice, intermittent dry cough, and weakness was presented to an endocrine surgeon. Thyroid pathology included signs of hypothyroidism treated with Thyroxine 112.5 µg and a nodule in the left lobe. The lesion is located on the posterior aspect of the lobe, which could probably be a cause of RLN involvement. Fine needle aspiration biopsy (FNAB) was performed twice with Bethesda category 2 result. Fibrolaryngoscopy (FLS) revealed the median position of the left vocal cord. Idiopathic, laryngeal, and thyroid causes of the VCP were excluded. Additionally, the patient displayed her anamnesis of the endometrial clear cell carcinoma following hysterectomy, external beam radiation therapy, and chemotherapy. The mediastinal metastasis was revealed sixteen years later. A chest computed tomography (CT) with intravenous contrast was done. A bulky tumor was found right under the aortic arch. Subsequently, the voice complaints reduced significantly after 4 chemotherapy courses. Cancer progression had led to the appearance of lymph node metastases on the supraclavicular region. Following six months the 60-year-old patient had passed away.ConclusionA history of the disease should always be kept in mind when assessing a patient’s complaints. VCP in case of thyroid pathology and previous secondary malignancy may be caused by metastatic tumor anywhere along the RLN pathway. Such a rare case shows the importance of additional methods of examination which may avoid unnecessary thyroid surgeries.

The safety and efficacy of delayed surgery by simulating clinical progression of observable papillary thyroid microcarcinoma: a retrospective analysis of 524 patients from a single medical center.

When active surveillance (AS) is developed in the patients with low-risk papillary thyroid microcarcinoma (PTMC), a medical center needs to ensure the delayed operation that is caused by PTMC clinical progression to have the same prognosis as that of immediate operation. The objective of this study was to investigate the efficacy of delayed surgery by simulating clinical progression (tumor size enlargement and appearance of lymph node metastasis) of PTMCs with AS in a single medical center. We retrospectively analyzed the response to therapy in 317 papillary thyroid carcinoma patients treated with total thyroidectomy and post-operative radioactive iodine ablation. They were classified into three groups according to tumor size (group A ≤0.5 cm; group B >0.5cm and ≤1 cm; group C >1cm and ≤1.5 cm) or two groups according to the presence (cN1) or absence (cN0) of the clinical lymph node (LN) metastasis. Groups C and cN1 were regarded as simulated clinical progression of observational PTMC and the operation for them was assumed to be "delayed surgery". However, Groups A, B and cN0 were regarded as no clinical progression and the operation for them was considered as immediate surgery. There were no significantly differences in excellent response to therapy and recurrence-free survival not only among the group A, B and C, but also between the group cN0 and cN1. In other words, these insignificant differences were found between immediate and simulated "delayed" surgeries. For the PTMC patients suitable for AS, the oncological outcomes were also excellent even if surgery was delayed until after the presence of clinical progression, according to our clinical simulation. Furthermore, we consider that it was feasible for medical centers to assess the ability to implement AS for PTMC patients by retrospectively analyzing their own previous clinical data using the described simulation.

Head and neck cancers of unknown primary: A diagnostic and therapeutic challenge

Abstract Head and neck cancers of unknown primary (CUP) represent up to 10% of all cancers located in the head and neck. True cancers of unknown primary, which remain of undetected primary origin after a correct clinical, imaging, surgical evaluation, have a reported frequency of between 1% and 2%. Cancers of unknown primary of the head and neck are a diagnostic challenge, considering that their main clinical manifestation is represented by the appearance of lymph node metastases in the cervical region. In general, the detection of cancers with an unknown starting point is late, difficult, with significant therapeutic failure. The diagnostic-therapeutic approach starts from the histopathological structure of the lymph node metastasis and continues with a correct and complete imaging evaluation. In this review are presented the diagnosis and therapeutic challenges and importance of head and neck cancers with unknown primary.

The Lymph Node Microenvironment May Invigorate Cancer Cells With Enhanced Metastatic Capacities.

Cancer metastasis, a typical malignant biological behavior involving the distant migration of tumor cells from the primary site to other organs, contributed majorly to cancer-related deaths of patients. Although constant efforts have been paid by researchers to elucidate the mechanisms of cancer metastasis, we are still far away from the definite answer. Recently, emerging evidence demonstrated that cancer metastasis is a continuous coevolutionary process mediated by the interactions between tumor cells and the host organ microenvironment, and epigenetic reprogramming of metastatic cancer cells may confer them with stronger metastatic capacities. The lymph node served as the first metastatic niche for many types of cancer, and the appearance of lymph node metastasis predicted poor prognosis. Importantly, multiple immune cells and stromal cells station and linger in the lymph nodes, which constitutes the complexity of the lymph node microenvironment. The active cross talk between cancer cells and immune cells could happen unceasingly within the metastatic environment of lymph nodes. Of note, diverse immune cells have been found to participate in the formation of malignant properties of tumor, including stemness and immune escape. Based on these available evidence and data, we hypothesize that the metastatic microenvironment of lymph nodes could drive cancer cells to metastasize to further organs through epigenetic mechanisms.

Regional lymph nodes and hematogenous metastasis of cancer

Aim. Morphological study of the microvasculature of regional lymph nodes in relation to the cancer of the lymph nodes as possible additional or alternative metastasis pathways. Methods. The lymph nodes of 150 cancer patients (1263 nodes in total), regional to cancer of various localization, were studied. Histological sections staining with hematoxylin and eosin by Van-Giesons method, pyronine by Brachets method, toluidine blue and picro-Mallory were prepared. An immunohistochemical study was performed using monoclonal antibodies to pan-cytokeratins, CD31, type IV collagen, CD3, CD20, and CD68. The area of metastases to the lymph nodes was determined by using a morphometric grid and used to identify the four study groups. In addition, the immunomorphological reactions of the lymph nodes were taken into account in each group. Results. It was identified that the microvasculature of the lymph nodes can be involved in the metastatic process along with the lymphatic pathways. At the same time, there is a decrease in vascular wall function and violation of the rheological properties of blood, accompanied by the deposition of intra- and extravascular fibrin. Hematogenous metastasis is largely influenced by the state of lymph node sinuses, in which blood is found, and in some observations by the expression of CD31 (a marker of blood endothelium). Hematogenous dissemination of cancer often begins after the appearance of lymph node metastases. The greater the anatomical extent of lymph node metastases, the more often tumor cells are present in the blood vessels. In addition, an isolated lesion of the microvasculature with the presence of tumor cells in the extranodal vessels without metastases in the lymph node itself was revealed. It was observed that the invasion of tumor cells into the microvasculature depended on the immunomorphological reactions of the lymph nodes. Conclusion. The microvasculature of regional lymph nodes can be both an additional and an alternative lymphogenous metastasis pathway of cancer; at the same time, vascular invasion is accompanied by microcirculation disorders and depends on the volume of metastases and the immunomorphological reactions of the lymph nodes.

A risk factor analysis of complications after surgery for vulvar cancer

IntroductionDespite the less frequent use of surgery in patients with vulvar cancer, the high rates of postoperative complications are still a matter of concern. The aim of the present study was to identify risk factors that influence postoperative complications rates in vulvar cancer and identify specific clinical parameters that may influence their incidence.MaterialsPatients who underwent curative-intent surgery for squamous cell carcinoma of the vulva from 2003 to 2018 were selected. All patient characteristics were analyzed as risk factors for the development of postoperative lymphocele, lymphedema, and wound dehiscence. The patients were followed up for 2 years postoperatively.ResultsThe investigation comprised 121 patients, of whom 18.1% developed wound dehiscence, 17.7% a lymphocele, and 20.4% lymphedema. We found no significant evidence of an association between patient’s characteristics and postoperative complications. The depth of tumor invasion and the appearance of lymph-node metastasis were significantly associated with postoperative complications. Free resection margins of 5 mm or more were associated with a reduced risk of postoperative complications compared to resection margins less than 5 mm. No complications were encountered after sentinel node biopsy (SNB). Complication rates were associated with inguinofemoral lymphadenectomy, but not with the extent of lymphadenectomy. The development of a lymphocele or wound dehiscence may be correlated with the development of long-term lymphedema.ConclusionFIGO stage at diagnosis influences the risk of postoperative complications. The use of SNB minimized postoperative complications. Correlations between the free microscopic resection margin distance and the risk of postoperative wound dehiscence must be investigated further.

Active surveillance in papillary thyroid carcinoma: not easily accepted but possible in Latin America.

To determine the percentage of patients with papillary thyroid carcinoma (PTC) who accepted active surveillance as an alternative to surgery in our clinical practice and to describe the clinical characteristics and outcomes of patients with Bethesda category V and VI thyroid nodules who chose active surveillance. We included 136 PTC patients from the Hospital de Clínicas, University of Buenos Aires without (i) US extrathyroidal extension, (ii) tumors adjacent to the recurrent laryngeal nerve or trachea, and/or (iii) US regional lymph-node metastasis or clinical distant metastasis. PTC progression was defined as the presence of i) a tumor larger than ≥ 3 mm, ii) novel appearance of lymph-node metastasis, and iii) serum thyroglobulin doubling time in less than one year. For patients with these features, surgery was recommended. Only 34 (25%) of 136 patients eligible for active surveillance accepted this approach, and around 10% of those who accepted abandoned it due to anxiety. The frequency of patients with tumor enlargement was 17% after a median of 4.6 years of follow-up without any evidence of nodal or distant metastases. Ten patients who underwent surgical treatment after a median time of 4 years of active surveillance (AS) had no evidence of disease after a median of 3.8 years of follow-up after surgery. Although not easily accepted in our cohort of patients, AS would be safe and easily applicable in experienced centers.

Clinical Trials of Active Surveillance of Papillary Microcarcinoma of the Thyroid.

Background The incidence of thyroid cancer is increasing globally. This is mainly due to the increase in the detection of small papillary carcinomas, including papillary microcarcinomas (PMC) 1 cm or smaller. It was suggested recently that PMCs are overdiagnosed and overtreated.MethodsIn 1993, the author proposed a clinical trial to compare surgery and observation for low-risk PMC at doctors’ meeting in Kuma Hospital, which was approved and the trial started in the same year. Patients choose immediate surgery or observation. This paper shares our 22-year experience with the active surveillance of more than 2000 patients with low-risk PMC and compares the outcomes of immediate surgery with that of active observation.ResultsThe oncological outcomes of these management groups were similarly excellent. In our active surveillance trial on 1235 patients, 8 % of patients showed tumor enlargement by 3 mm or more at 10 years of observation, and 3.8 % of the patients showed novel appearance of lymph node metastasis at 10 years. Patients 40 years or younger tended to show progression of the disease. Patients with these slight progressions of the disease were successfully treated with a rescue surgery. None of the patients in both study groups died of the disease. However, incidences of unfavorable events, such as temporary vocal cord paralysis (VCP) and temporary and permanent hypoparathyroidism, were significantly higher in the immediate surgery group than in the observation group (4.1 vs. 0.6 %, p < 0.0001; 16.7 vs. 2.8 %, p < 0.0001; and 1.6 vs. 0.08 %, p < 0.0001, respectively). Permanent VCP occurred in two of the surgery group.ConclusionsAs a result, although we still offer two options, immediate surgery or observation, to patients with low-risk PMC at Kuma Hospital, we now strongly recommend observation as the best choice.

Effects of Pregnancy on Papillary Microcarcinomas of the Thyroid Re-Evaluated in the Entire Patient Series at Kuma Hospital.

Background: An active-surveillance clinical trial of low-risk papillary microcarcinoma (PMC) patients has been performed at the authors' institution, Kuma Hospital, since 1993. Favorable oncological results have been reported. During the trial, a few patients were encountered with PMC that showed enlargement during pregnancy, and these cases have been reported. During pregnancy, a large amount of human chorionic gonadotropin (hCG) having weak thyrotropin (TSH) activity is produced, possibly affecting the progression of PMC. This study investigated how pregnancy and delivery influenced the progression of PMC in the entire active surveillance PMC patient series.Methods: From 1993 to 2013, 1841 patients with low-risk PMC chose the active surveillance program. Fifty of the 1549 female PMC patients experienced 51 pregnancies/deliveries. To minimize observer variation, a single specialist sonographer re-evaluated the changes in the size of these 50 patients' PMCs before and after the pregnancies/deliveries.Results: Four patients (8%) showed enlargement of PMC by ≥3 mm; one patient (2%) showed a decrease by ≥3 mm, and the remaining 44 patients (45 events, 90%) showed stable disease. None of the patients had a novel appearance of lymph node metastases during pregnancy. Of the four patients with enlargement, two underwent surgery after delivery, and the other two continued the active surveillance, since their tumors did not grow after the delivery. After delivery, the PMC of one of these four patients remained stable, and another showed a decrease in PMC size. To date, six more PMC patients underwent surgery after delivery for reasons other than disease progression due to pregnancy and delivery: two opted out of active surveillance, two were identified with a nodal metastasis during active surveillance after delivery, one had Graves' disease, and one showed enlargement of nodules of the contralateral lobe.Conclusions: Pregnancy and delivery was associated with an increase in size of PMCs in only 8% of the 51 pregnancies/delivery cases. None of the patients developed nodal metastasis during pregnancy. Thus, a possible future pregnancy does not prevent such patients from undergoing active surveillance, although watchful observation during pregnancy is recommended.

Patient Age Is Significantly Related to the Progression of Papillary Microcarcinoma of the Thyroid Under Observation

We showed previously that subclinical low-risk papillary thyroid microcarcinoma (PTMC) could be observed without immediate surgery. Patient age is an important prognostic factor of clinical papillary thyroid carcinoma (PTC). In this study, we investigated how patient age influences the observation of low-risk PTMC. Between 1993 and 2011, 1235 patients with low-risk PTMC chose observation without immediate surgery. They were followed periodically with ultrasound examinations. These patients were enrolled in this study. We divided them into three subsets based on age at the beginning of observation: young (<40 years), middle-aged (40-59 years), and old patients (≥60 years). Observation periods ranged from 18 to 227 months (average 75 months). We set three parameters for the evaluation of PTMC progression: (i) size enlargement, (ii) novel appearance of lymph-node metastasis, and (iii) progression to clinical disease (tumor size reaching 12 mm or larger, or novel appearance of nodal metastasis). The proportion of patients with PTMC progression was lowest in the old patients and highest in the young patients. On multivariate analysis, young age was an independent predictor of PTMC progression. However, none of the 1235 patients showed distant metastasis or died of PTC during observation. Although only 51 patients (4%) underwent thyrotropin (TSH) suppression based on physician preference, the PTMC of all patients enrolled in this TSH suppression study, except one, were clinically stable. To date, 191 patients underwent surgery for various reasons after observation. None showed recurrence except for one in the residual thyroid, and none died of PTC after surgery. Old patients with subclinical low-risk PTMC may be the best candidates for observation. Although PTMC in young patients may be more progressive than in older patients, it might not be too late to perform surgery after subclinical PTMC has progressed to clinical disease, regardless of patient age.

Die Wertigkeit der Lymphadenektomie beim muskelinvasiven Urothelkarzinom der Harnblase - Ein Überblick über die aktuelle Datenlage

The extent of the lymphadenectomy (LAE) as well as the appearance of lymph node metastasis are important prognostic factors in the treatment of the muscle invasive transitional cell carcinoma of the bladder (TCC). However there is still the need to discuss the dimension of the LAE. Pubmed was searched with regard to guidelines for the treatment of muscle invasive TCC. In particular, operation techniques, the appearance of lymph node metastasis, lymph node mapping, histopathological and radiological detection methods, as well as the risk of positive lymph nodes were analysed. The confirmation of lymph node metastasis is associated with a poorer outcome. Besides knowledge of metastasis pathways, an extensive and careful pathological reprocessing is one cornerstone of the procedure. Molecular markers seem to support the detection of micrometastasis. The extended LAE is associated with a better long-term survival rate compared to the limited LAE. New operation techniques such as laparoscopic or robot-assisted cystectomy are associated with lower peri- and postoperative morbidity, but the extended LAE is more challenging using these techniques. There are no long-term results available yet for these methods. Most data regarding lymphadenectomy and survival rate are based on retrospective studies thus decreasing the level of evidence. An extended LAE shows retrospectively a better outcome in patients with lymph node metastasis in TCC. Therefore an extended LAE should be performed in patients with muscle invasive TCC. New methods for detecting lymph node metastasis are elevating the confirmation rate.

Treatment of N in the Upper Maxillary Tumors

From 2002 to 2008, 86 patients have undergone surgical treatment of malignant upper maxillary tumors at the Maxillo-Facial Surgery Department, Tor Vergata University, Rome. All the N-positive patients at the time of the T therapy have undergone lymph node surgical emptying. In 6 patients, a laterocervical emptying was performed when laterocervical metastases were found. In the remaining 68 patients, with no evidence of N, we did not perform laterocervical emptying. We found in our patients a high percentage of cervical metastasis in T2 squamous cell carcinoma of the maxilla (32.1%). In this article, the authors present the results of their experience in treating N in upper maxillary tumors. This research study highlights some important aspects that have to be considered. Squamous cell carcinoma of the maxilla extending to the oral cavity (T1-T2) shows a higher laterocervical lymphophily than the superoposterior ones (T3-T4). Presence or appearance of lymph node metastases is a high-malignancy index, with a subsequently very negative prognosis. Considering the large percentage of cervical recurrences in T1-T2 squamous cell carcinoma of the maxilla that spread up in the hard palate mucosa and upper gum and the consequently high morbidity, performing a prophylactic laterocervical emptying in these patients could be advisable. Even in the recent literature, we found opinion in favor of this behavior.

Correlation between disease progression and histopathologic criterions of the lip squamous cell carcinoma

The most common malignancy of the lip is squamous cell carcinoma (SCC). In our population, according to epidemiological data, almost a half of all (45%) SCC of oral mucous tissue spreads over the lower and upper lip. The aim of this study was to estimate prognostic importance of histopathologic characteristics--histologic grade, nuclear grade and tumor size in relation to the appearance of lymph node metastases and relapse in SCC of the lip. In the retrospective-prospective study 70 cases of lower and upper lip SCC were analyzed. They were diagnosed from 2002 to 2006 in the Clinic of Maxillofacial Surgery, Clinical Center of Montenegro. The data about localization of the carcinomas, histopathologic characteristics and lymph node status were taken from medical files of the patients. The patients were followed up in a 3-year period and the disease relapse or/and metastatic disease appearance were registereds. There was statistically significant difference in tumor size among the patients with and without disease relapse (p = 0.027). Logistic regression analysis showed that the tumor size is a statistically significant factor (R = 0.186; p = 0.011) for the appearance of regional lymph node metastases. Relative risk [exp (B)] for the appearance of regional lymph node metastases in relation to tumor size was 2.807. Histologic and nuclear grade of lip SCC are not prognostic factors for the appearance of the disease relapse and regional lymph node metastases. Tumor size is a predictive factor of the relapse appearance, as well as for lymph node metastases appearance. In clinical practice, tumor size is a factor that classifies patients with lip SCC into the groups of higher and smaller risk of relapse appearance and for lymph node metastases appearance. Our results suggest that, risk for lymph node metastases appearance increases 2.8 times with increasing of the tumor size over 2 cm in diameter.

Sentinel node biopsy for early oral and oropharyngeal squamous cell carcinoma

The appearance of lymph node metastases represents the most important adverse prognostic factor in head and neck squamous cell carcinoma. Therefore, accurate staging of the cervical nodes is crucial in these patients. The management of the clinically and radiologically negative neck in patients with early oral and oropharyngeal squamous cell carcinoma is still controversial, though most centers favor elective neck dissection for staging of the neck and removal of occult disease. As only approximately 30% of patients harbor occult disease in the neck, most of the patients have to undergo elective neck dissection with no benefit. The sentinel node biopsy concept has been adopted from the treatment of melanoma and breast cancer to early oral and oropharyngeal squamous cell carcinoma during the last decade with great success. Multiple validation studies in the context of elective neck dissections revealed sentinel node detection rates above 95% and negative predictive values for negative sentinel nodes of 95%. Sentinel node biopsy has proven its ability to select patients with occult lymphatic disease for elective neck dissection, and to spare the costs and morbidity to patients with negative necks. Many centers meanwhile have abandoned routine elective neck dissection and entered in observational trials. These trials so far were able to confirm the high accuracy of the validation trials with less than 5% of the patients with negative sentinel nodes developing lymph node metastases during observation. In conclusion, sentinel node biopsy for early oral and oropharyngeal squamous cell carcinoma can be considered as safe and accurate, with success rates in controlling the neck comparable to elective neck dissection. This concept has the potential to become the new standard of care in the near future.

A microRNA DNA methylation signature for human cancer metastasis

MicroRNAs (miRNAs) are small, noncoding RNAs that can contribute to cancer development and progression by acting as oncogenes or tumor suppressor genes. Recent studies have also linked different sets of miRNAs to metastasis through either the promotion or suppression of this malignant process. Interestingly, epigenetic silencing of miRNAs with tumor suppressor features by CpG island hypermethylation is also emerging as a common hallmark of human tumors. Thus, we wondered whether there was a miRNA hypermethylation profile characteristic of human metastasis. We used a pharmacological and genomic approach to reveal this aberrant epigenetic silencing program by treating lymph node metastatic cancer cells with a DNA demethylating agent followed by hybridization to an expression microarray. Among the miRNAs that were reactivated upon drug treatment, miR-148a, miR-34b/c, and miR-9 were found to undergo specific hypermethylation-associated silencing in cancer cells compared with normal tissues. The reintroduction of miR-148a and miR-34b/c in cancer cells with epigenetic inactivation inhibited their motility, reduced tumor growth, and inhibited metastasis formation in xenograft models, with an associated down-regulation of the miRNA oncogenic target genes, such as C-MYC, E2F3, CDK6, and TGIF2. Most important, the involvement of miR-148a, miR-34b/c, and miR-9 hypermethylation in metastasis formation was also suggested in human primary malignancies (n = 207) because it was significantly associated with the appearance of lymph node metastasis. Our findings indicate that DNA methylation-associated silencing of tumor suppressor miRNAs contributes to the development of human cancer metastasis.

Prognostic role of microvascularization in surgically treated lung cancer

The aim of our study was the determination of microvascularization and its prognostic significance in lung cancer patients. Histological sections were prepared from paraffin-embedded tissues removed from the peripheral part of the tumor of 450 radically operated non-small cell and small cell lung cancer patients. Immunohistochemical staining was performed with antibody against factor VIII-associated antigen. During computer imaging, the absolute and relative parameters of vascularization were determined, as was the density of tumor cells situated to the nearest neighboring vessels. The results were compared with TNM status, the cell type and survival. T2 and T4 tumors demonstrated an enhanced vascularization, however, except for the surface fraction, statistically significant difference was not found. The microvascularization parameters did not differ significantly between tumors with different N status. In small cell lung cancer cases, the vascularization was stronger than in non-small cell lung cancer cases, while cell density was lower, however, these differences did not prove statistically significant. The survival rate decreased significantly with the increasing tumor cell density in the interval of 0-20 microm. A clear connection could not be demonstrated between vascularization and the appearance of lymph node metastases. The density of tumor cells measured in the direct vicinity of vessels proved an important prognostic factor.

Prognostic significance of microvascularization in cases of operated lung cancer

Measurement of microvascularization and determination of its prognostic significance in cases of lung cancer. Section prepared from histological material from 432 radically operated non-small cell lung cancer patients were stained with antibodies against factor VIII-associated antigen. During computer imaging, the absolute and relative parameters of the vascularization were determined, as was the density of tumour cells situated in the vicinity of the vessels. The results were compared with the TNM status, the cell type and the survival. Each parameter demonstrated an enhanced vascularization in classifications T2 and T4, but only the surface fraction, the mean vascular circumference and the mean vascular area displayed a significant change. The microvascularization parameters did not differ significantly between with different N status, however, the cell density progressively increased in the areas close to the vessels in advanced pN classifications. Elevation of the tumour cell density within 20 microm distance of the vessels was accompanied by a significantly poorer survival rate. The density of tumour cells within 20 microm region was the second strongest prognostic factor after the N status. More advanced tumour classifications grow with enhanced vascularization. A clear-cut connection cannot be demonstrated between the vascularization and appearance of lymph node metastases. The density of tumour cells measured in the direct vicinity of vessels is an important prognostic factor.

Immunohistochemical analysis of lymphocytic infiltration in the tumor microenvironment in patients operated on for laryngeal cancer.

The aim of this study was to evaluate semiquantitative and qualitative analysis of lymphocytic infiltrations in a neoplasm microenvironment in patients with laryngeal cancers and the correlation analysis between the intensitivity degree and composition of lymphocytic infiltration in foreseeing a survival time and probability of the appearance of lymph node metastases. Postoperative specimens from 43 patients (Upper Silesia region) operated on for laryngeal cancer in the 2nd ENT Department, Silesian Medical University in Zabrze between 1985 and 1995 all had unfavorable courses due to tumor recurrences. The patients' ages ranged from 39 to 79 years (mean 57 years). Tissue specimens were subjected to routine processing. The degree of pathological changes was ascertained and immunohistochemical preparations of laryngeal tissue were prepared according to generally accepted methods. The following primary monoclonal antibodies were used: CD 3, CD 20, CD 43, CD 45 RO, CD 56. The distribution analysis of the intensity of the phenotype CD 43 evaluated the lymphocytic infiltration in relation to differentiation of the whole study group. The intensity of CD 43 cell infiltration increased in the group of patients with lymph node metastases. In patients with stage IV disease, a relationship was found between survival time and intensity of cell infiltrations with CD 43 and CD 45 RO lymphocytes. The influence of these two lymphocyte phenotypes in the patient subgroups - one after total laryngectomy with confirmed lymph node metastases and the other group without lymph node metastases - showed their prognostic value. Our analysis of lymphocytic infiltration, mostly of CD 43 cells, in the neoplasm microenvironment indicated a prognostic value for determining a shorter survival time and the possibility of lymph node metastases in patients with recurrences of cancer.

Intact Vitronectin Induces Matrix Metalloproteinase-2 and Tissue Inhibitor of Metalloproteinases-2 Expression and Enhanced Cellular Invasion by Melanoma Cells

The initial site of melanoma cell metastasis is frequently the regional lymph nodes, and the appearance of lymph node metastasis correlates with poor prognosis. Lymph node adhesion is mediated by an interaction between the tumor cell integrin alphavbeta3 and lymph node vitronectin. In this study, we explored the relationship between adhesion and proteolysis by examining the direct effect of vitronectin receptor ligation on matrix metalloproteinase-2 (MMP-2) production by B16F1 and B16F10 melanoma cells. We report a dose-dependent increase in secretion of both MMP-2 and tissue inhibitor of metalloproteinases-2 (TIMP-2) in response to vitronectin. Cellular invasiveness was also enhanced by vitronectin, as shown by the increased ability of vitronectin-treated cells to invade a synthetic basement membrane (Matrigel). Both the vitronectin-induced MMP-2 production and vitronectin-enhanced invasion were blocked by the peptide ligand Arg-Gly-Asp-Ser (RGDS). Furthermore, neither plasmin-degraded vitronectin nor the peptide ligand RGDS stimulated MMP-2 secretion or invasiveness, indicating that a multivalent ligand-receptor interaction rather than simple receptor occupancy was required for MMP-2 induction. MMP-2 and MMP-2/TIMP-2 interaction with the plasma membrane of melanoma cells resulted in enhanced catalytic activity against 14C-labeled gelatin, suggesting that membrane association may function in posttranslational regulation of MMP-2 activity. This is supported by data showing increased cellular invasion by cells containing membrane-bound MMP-2. Binding of proMMP-2 and proMMP-2/TIMP-2 to melanoma cells was not inhibited by RGDS, and melanoma cell adhesion to vitronectin was unaffected by pro- or active MMP-2, indicating that MMP-2 did not interact with the murine vitronectin receptor. Together, these data provide evidence for a functional link between adhesion and proteolysis and suggest a potential mechanism whereby adhesion of an invasive cell to the extracellular matrix regulates subsequent invasive behavior.