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PubMed2003

Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis.

Tumor cell migration into the lymph nodes is an important aspect of cancer, yet little is known about the processes involved. CCR7 has been shown to play an important role in tumor cell migration and lymph node metastasis. The aim of our study was to evaluate the expression of CCR7 in nonsmall cell lung cancers (NSCLCs). We investigated CCR7 expression in 71 patients with NSCLC who underwent curative tumor resection by means of reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. CCR7 mRNA was expressed in 45 cases (63.3%). The CCR7 mRNA expression was significantly associated with lymph node metastasis, stage, lymphatic invasion, CCR7 protein and CXCR4 protein (p = 0.0001 for lymph node metastasis; p < 0.0001 for stage; p = 0.0454 for lymphatic invasion; p < 0.0001 for CCR7 protein; p = 0.0013 for CXCR4 protein). Twenty-six (57.8%) of 45 cases with CCR7 mRNA expression in their cancer tissues were node-positive, whereas only 3 (11.5%) of 26 cases without CCR7 mRNA expression were node-positive. Furthermore, expression of CCR7 mRNA was shown to be an independent predictor of lymph node metastasis by multivariate analysis (p = 0.0117). Our study demonstrates that CCR7 might be related to the development of lymph node metastasis in NSCLC. The expression of CCR7 mRNA could open up a new window for the diagnostic staging and treatment of NSCLC.

Aged↗

PubMed2006

MR contrast agents in lymph node imaging.

The detection of tumor metastases in lymph nodes is clinically important for tumor staging and therapy planning in cancer patients. However, differentiating between malignant and benign lymph nodes is still a problem because current imaging modalities rely only on the size and shape of the lymph nodes. Thus, small metastases in normal-sized lymph nodes can be missed, and it is difficult to differentiate enlarged nodes (benign hyperplasia versus malignant disease). Therefore, a specific lymphotropic contrast agent is needed to obtain a high contrast between functional and metastatic tissue. Contrast-enhanced MR lymphography is a noninvasive method for the analysis of the lymphatic system after interstitial (intracutaneous or subcutaneous) or intravenous application of contrast media. Interstitial MR lymphography using extracellular, liposomal, polymeric, lipophilic or particulate contrast agents results in high accumulation in regional lymph nodes. The systemic administration of a lymphotropic contrast medium is needed to address each individual lymph node. Ultrasmall superparamagnetic iron oxide particles are in late-stage clinical development for this indication, but they take 24h to show sufficient contrast. Recently, a gadolinium-type contrast agent (Gadofluorine M) was described that detected lymph node metastases within 60 min of intravenous injection.

Contrast Media↗

PubMed1998

Lymphocyte surface marker and cytokine expression in peripheral and mucosal lymph nodes.

Lymphocyte populations, adhesion molecule and cytokine expression were determined in lymph nodes draining peripheral (popliteal and prescapular) or mucosal (abomasal and jejunal) tissue sites using flow cytometry analysis, immunostaining and cytokine-specific reverse-transcription-polymerase chain reaction (RT-PCR). Similar proportions of lymphocyte subpopulations were present in all lymph nodes except for immunoglobulin A+ (IgA+) B cells which were only present in significant numbers in the gastrointestinal lymph nodes. Peripheral lymph nodes contained a significantly higher number of CD4+ cells expressing L-selectin and beta 1-integrin than mucosal lymph nodes while the alpha 4-integrin chain was expressed at similar levels in all lymph nodes. The peripheral node adressin recognized by the MECA 79 monoclonal antibody (mAb) was mainly expressed on peripheral lymph node vessels. RT-PCR analysis showed that interleukin (IL)-10 and IL-4 were preferentially induced in the gastrointestinal lymph nodes while IL-2 and interferon-gamma (IFN-gamma) were induced in all lymph nodes after polyclonal stimulation. These results indicate that there are substantial differences in the cell populations and microenvironments of lymph nodes draining mucosal and peripheral tissue sites in adult sheep.

Animals↗

PubMed1981

Nonlymphoid hematopoietic malignant disease of the lymph nodes.

The extension of myeloproliferative malignant tumors to lymph nodes was studied in seven excision biopsies and 27 autopsies in which lymph nodes were obtained from all nodal regions. We observed the proliferation of poorly, partially, and well differentiated neoplastic cells with a predominance of immature cells of the granulocytic series and fewer cells of the erythroid and megakaryocytic cells lines. Disturbances of the lymph node architecture consisted of invasion by abnormal cells of the trabecular stroma, disrupting the reticulin mesh and extending toward the pericapsular area. In the lymph node a loose network of thin and thick fibers replaced the original framework. Generalized lymph node involvement at autopsy showed preservation of the architecture, both in cases with total replacement of the lymphoid population by abnormal cells and in cases with involvement by single cells or small groups of cells. Partial involvement occurred chiefly in the medullary zone, probably the result of hematogenous dissemination from the vascular plexus in medullary cords. Further abnormal cell development was linked to trabecular infiltration. The extensive involvement seen at autopsy took place by lymphatic dissemination. In lymph nodes studied at autopsy an abnormal immunoblastic reaction was observed. At first these abnormal cells were suspected of representing the myeloproliferative malignant disease, but the application of special staining techniques revealed their polyclonal cytoplasmic immunoglobulins. The chloroacetate esterase stain and the immunohistochemical stains for muramidase and hemoglobulin were especially useful in demonstrating that myeloproliferative diseases develop in the environment found in lymph nodes.

Adult↗

PubMed2006

Significance of multiple lymphatic basin drainage in truncal melanoma patients undergoing sentinel lymph node biopsy.

BACKGROUND: Truncal melanoma involving metastases to multiple lymph node basins has a much worse prognosis than tumor involvement of a single lymph node basin. Recent results also suggest that, independently of the status of lymph node involvement, patients with multiple lymphatic basin drainage (MLBD) on lymphoscintigraphy have an increased risk of lymph node metastasis and a worse prognosis than those with a single lymphatic drainage basin. Because published reports have conflicting results, the authors compared their experience at the University of Michigan Comprehensive Cancer Center with recently published findings. METHODS: The authors searched a prospectively maintained melanoma database at the University of Michigan for patients with primary truncal melanoma who underwent lymphoscintigraphy and sentinel lymph node biopsy between 1997 and 2004. The association of MLBD with the clinical and pathologic characteristics collected and the presence of regional metastases was tested by using contingency tables and the chi(2) test statistic and by using the Fisher's exact test statistic when cell frequencies were small. The product-limit method of Kaplan and Meier was used to estimate disease-free and overall survival probabilities. RESULTS: Of 423 patients with primary truncal melanoma who underwent sentinel lymph node biopsy, 123 (29%) had a positive result, and 98 patients (23.2%) had MLBD. Patients with tumors located in the middle of the trunk and tumor ulceration were more likely to have MLBD (P < .0001 and P = .045, respectively). Patients with a single lymphatic drainage basin and MLBD had a similar risk of lymph node metastasis and similar disease-free and overall survival. CONCLUSIONS: Patients with truncal melanomas tend to have MLBD when the tumor is located in the middle of the trunk or when ulceration is present. In our experience, drainage to multiple lymphatic basins was not an independent risk factor for sentinel lymph node metastasis and has no independent prognostic significance.

Adolescent↗

PubMed2003

Granulocytic sarcoma presenting with lymph node infarction at disease onset.

A completely infarcted lymph node is an unusual event. However, lymph node infarction should alert the pathologist to the considerable likelihood of malignant lymphoma. We report two unusual cases of acute myeloid leukemia presenting with granulocytic sarcoma at disease onset with a lymph node lesion exhibiting extensive lymph node infarction. The infarcted tissue contained numerous eosinophilic cell ghosts. There were some islands of degenerated, pyknotic medium-sized nuclei resembling lymphoblasts present in the necrotic area. By immunohistochemistry, these medium sized cells were CD3-, CD20-, CD34+, CD43+, CD45RO-, CD68-, CD79a- and myeloperoxidase+ in both cases. Differentiation of granulocytic sarcoma from malignant lymphomas is important for adequate therapy. The present cases indicate that granulocytic sarcoma should be added to the list of differential diagnoses for lymph node infarction.

Acute Disease↗

PubMed2001

Value of lymph node dissection during resection of intrahepatic cholangiocarcinoma.

BACKGROUND: Hepatectomy with extensive lymph node dissection is the standard operation for intrahepatic cholangiocarcinoma (IHCC). However, lymph node dissection may not always be effective at reducing tumour recurrence. METHODS: Forty-nine patients with IHCC who underwent hepatectomy were investigated to determine patterns of tumour recurrence and to estimate the value of lymph node dissection during resection. RESULTS: At hepatectomy most metastatic lymph nodes were identified at least to the level of group 2 lymph nodes. Among 23 patients who developed recurrence, 17 had liver metastases and the other six had recurrence at other sites, mainly in the peritoneum. Poorly differentiated histology was related to the development of liver metastases. No patient with the intraductal growth type of IHCC had tumour recurrence. Lymph node dissection did not appear to improve patient survival. Histological findings of lymph node metastases and intrahepatic metastases were independent indicators of poor prognosis. CONCLUSION: Lymph node metastases were seldom limited to the regional lymph nodes; most tumour recurrence occurred in the liver. Lymph node dissection did not appear to improve patient survival. Lymph node dissection alone is not likely to improve the prognosis without further control of liver metastases.

Bile Duct Neoplasms↗

PubMed2002

The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes.

Malignant lymphocyte migration into lymph nodes is an important aspect of chronic lymphocytic leukemia (CLL), yet little is known about the processes involved. Here we demonstrate that CLL cells migrate across vascular endothelium in response to at least 3 chemokines, namely, CCL21, CCL19, and CXCL12. Moreover, transendothelial cell migration (TEM) in response to CCL21 and CCL19 was significantly higher for the malignant B cells of patients who had clinical lymph node involvement as compared with those of patients lacking such organomegaly. Furthermore, the expression of CCR7, the receptor for both CCL21 and CCL19, correlated with clinical lymphadenopathy, and blocking of CCR7 inhibited CLL cell TEM. By using immunohistochemistry we demonstrated that CCL21 and CCL19, but not CXCL12, are located in high endothelial venules and are, therefore, in an appropriate location to induce TEM. Regarding the adhesion receptors involved in TEM, alpha4 (most likely in association with beta1) and alphaLbeta2 were shown to be important in CLL cell TEM in vitro, but only the level of alpha4 expression correlated with the presence of clinical lymphadenopathy. The present studies are the first to shed light on the factors determining CLL cell entry into nodes and define the phenotype of circulating malignant cells likely to determine the pattern of lymph node enlargement in the disease.

Aged↗

PubMed1990

[Critical evaluation of 245 cases of lymph node biopsy].

We examined 245 lymph node biopsies of subjects possibly suffering from systemic lymphopathy, in which non-invasive means did not allow a certain diagnosis. The parameters considered are: histological finding, age of patients at the time of diagnosis, presence of general symptoms, location of the superficial lymph nodes concerned, collateral tests usually performed, familiarity. The significance of differences between the main disease groups has been checked by the usual statistical methods. Our data are generally consistent with the diagnostic criteria commonly accepted in the literature, except for some details: e. g. in Hodgkin's disease the distribution of patient ages at the time of first diagnosis shows a single peak (unimodal), instead of two, as described in other countries. The involvement of supraclavicular nodes in chronic aspecific lymphopathies is less frequent than in systemic lymphomas. Our experience has widely confirmed the indications and usefulness of lymph node biopsy for hematological diagnosis.

Adolescent↗

PubMed2003

Biological markers in pT1 and pT2 ovarian cancer with lymph node metastases.

OBJECTIVE: A relatively high incidence of pelvic and paraaortic lymph node metastases is found in patients with pT1 and pT2 ovarian cancer. This paper investigates the clinicomorphological parameters and the expression of various biological markers in these tumors in order to define possible risk factors for lymphatic dissemination. METHODS: In a retrospective study we identified 51 patients with pT1 and pT2 ovarian cancer. All patients underwent total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and systemic pelvic +/- paraaortal lymphadenectomy. The incidence of lymph node metastases in these patients and the clinicomorphological parameters of their tumors were examined. Immunohistochemistry was used to determine the expression levels of the cell proliferation marker Ki-67, the cell adhesion molecules CD44s and CD44v6, and the oncoprotein HER2/neu of the tumors and their respective lymph node metastases. RESULTS: Lymph node involvement was found in 5 of 26 patients with pT1 ovarian cancer and in 6 of 25 patients with pT2 ovarian cancer. Serous adenocarcinoma was associated with a significantly higher incidence of lymph node metastases than other histological types (chi(2) = 4.7, P = 0.03). No correlation was found between tumor grade and the lymph node status. High Ki-67 expression was significantly correlated with spread to the lymph nodes (chi(2) = 4.2, P = 0.04), whereas expression of CD44s, CD44v6, and HER2/neu was not related to the lymph node status. Survival analyses showed no difference in disease-free and overall survival in patients with lymph node metastases compared to those without lymph node metastases. No association was seen among histological type, tumor grade, and immunohistochemically detected Ki-67, CD44s, CD44v6, and HER2/neu expression on the one hand and disease-free and overall survival on the other hand. CONCLUSIONS: Our data suggest that in early stage ovarian cancer the serous histological type and tumors showing a high Ki-67 expression carry a high risk of lymph node metastases. With respect to prognosis our data showed a minor role for Ki-67, CD44s, CD44v6, and HER2/neu expression and the occurrence of lymph node metastases in pT1 and pT2 ovarian cancer.

Adult↗

PubMedDate not supplied

Value of extended lymph node dissection in the treatment of gastric cancer.

Regional lymph node metastasis is a critical prognostic factor in gastric cancer, and extended lymph node dissection and routine microscopic examination of all resected nodes could potentially provide accurate information regarding lymph node status. On the other hand, the therapeutic value of extended lymph node dissection is controversial. While retrospective and prospective non-randomised comparative studies have shown that extended lymph node dissection significantly improves the survival rate, prospective randomised trials have failed to demonstrate the efficacy of extended dissection, although the number of patients in these studies was limited. The present review of the literature therefore considers the prognostic significance of regional lymph node metastases and the therapeutic efficacy of lymph node dissection performed for gastric cancer.

Clinical Trials as Topic↗

PubMed1999

Influence of application vehicle on skin sensitization to methylchloroisothiazolinone/methylisothiazolinone: an analysis using the local lymph node assay.

The murine local lymph node assay (LLNA) is a method for the identification of skin sensitizing chemicals in which activity is measured as a function of proliferative responses induced in draining lymph nodes following topical exposure of mice to the test material. More recently, the LLNA has also been used for the determination of relative skin sensitizing potency based upon the mathematical derivation of an EC3 value, this being the estimated concentration of test chemical necessary to provoke a 3-fold increase in lymph-node cell-proliferative activity compared with concurrent vehicle-treated controls. Here we describe the use of the LLNA to determine the influence of vehicle on the skin-sensitizing potency of methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), the active ingredient of preservatives such as Kathon CG. To this end, LLNA responses to MCI/ MI were measured using the vehicles 4:1 acetone:olive oil (AOO), methyl ethyl ketone, dimethylsulfoxide, dimethylformamide, propylene glycol (PG) and acetone. It was found that the vehicle in which MCI/MI was applied had a substantial impact on activity, with derived EC3 values varying from 0.0049% with AOO to 0.048% with PG. With the other vehicles, EC3 values ranged from 0.0068 to 0.0076%. The skin sensitizing potency of MCI/MI as judged from LLNA responses is consistent with what is known of the requirements for sensitization in humans. It is proposed that the LLNA not only provides a method for determination of relative skin sensitizing potency, but is also appropriate for assessing the influence of vehicle matrix on sensitizing activity.

Allergens↗

PubMedDate not supplied

Endosonographic features predictive of lymph node metastasis.

Endosonographic features that are thought to characterize lymph node metastasis were evaluated in 100 patients with esophageal carcinoma. Subjects underwent preoperative endoscopic ultrasonography to assess depth of tumor invasion (T stage) and lymph node metastasis (N stage). Endosonographically imaged lymph nodes were evaluated according to the following parameters: size, shape, border demarcation, and central echo pattern. Sensitivity and specificity of endosonography in detecting lymph node metastasis were 89.1% and 91.7%, respectively, when stringent criteria were used. When lymph nodes were imaged endosonographically, regardless of the specific features, the likelihood of N1 disease, was 86%, whereas when no lymph nodes were imaged, the chance of N0 disease was 79%. Endosonographic features predictive of malignancy in increasing order of importance were echo-poor (hypoechoic) structure, sharply demarcated borders, rounded contour, and size greater than 10 mm. Collectively, the EUS features produced an additive effect with respect to accuracy in the prediction of malignant lymph node involvement; malignancy could be predicted with 100% accuracy when all four features were present. These results demonstrate that a careful and systematic approach to the endosonographic assessment of lymph node metastasis can improve staging accuracy.

Aged↗

PubMed1996

Risk factors for lymph node metastasis from intramucosal gastric carcinoma.

BACKGROUND: Although regional lymph node metastasis from intramucosal early gastric carcinoma (EGC) is rare, it is very important to clarify the characteristics of patients having lymph nodal metastases in order to determine appropriate therapy. METHODS: The authors investigated 1196 patients with solitary intramucosal EGC who underwent resection at the National Cancer Center Hospital in Tokyo, with special reference to lymph node metastases. Eight clinicopathologic factors (age, sex, tumor: size, location, macroscopic type, histologic type, histologic ulceration of the tumor, and lymphatic vessel invasion) were investigated by univariate and multivariate analyses for their possible relationship to lymph node metastasis. RESULTS: Lymph node metastases were found in 43 patients (3.5%). Univariate analysis revealed that younger age (< 57 years), macroscopic depressed type, larger tumor size (> or= 30 mm), undifferentiated histologic type, histologic ulceration of the carcinoma, and lymphatic vessel invasion had a significant association with regional lymph node metastasis. Multivariate analysis revealed that lymphatic vessel invasion, histologic ulceration of the tumor, and larger size (> or = 30 mm) were independent risk factors for regional lymph node metastasis. The incidence of lymph node metastasis from intramucosal EGC negative for these 3 risk factors was only 0.36% (1 in 277 patients). CONCLUSIONS: Lymphadenectomy is unnecessary for patients with small intramucosal EGC with neither histologic ulceration of the tumor nor lymphatic vessel invasion because the incidence of regional lymph node metastasis is extremely low in those patients. The therapeutic options for such patients would be local resection or endoscopic resection.

Age Factors↗

PubMed2005

Modes of benign mechanical transport of breast epithelial cells to axillary lymph nodes.

The status of axillary lymph nodes is a key prognostic indicator available for the management of patients with breast cancer. Sentinel lymph node (SLN) evaluation as a predictor of lymph node status has led to increased use of ancillary methods, principally immunohistochemistry, to increase the sensitivity of the SLN biopsy. So-called "occult" micrometastases detected by such methods have led to speculation that some may have reached the SLNs by benign mechanical transport (BMT) rather than a metastatic process. We review evidence suggesting two potential modes of BMT: lymphatic transport of epithelial cells displaced by biopsy of the primary breast tumor and by breast massage-assisted SLN localization. The biopsy techniques under most scrutiny include fine needle aspiration and large-gauge core biopsy. The evidence implicating breast massage prior to SLN biopsy as a mode of BMT has been supported by statistical analysis; however, no method of distinguishing massage-associated cells in SLNs from true occult micrometastases is available. The significance of small epithelial clusters in SLNs is currently unknown. Thus, deviation from current biopsy and SLN-localizing practices is unwarranted.

Axilla↗

PubMed2004

[How to avoid the uncertainties of intraoperative examination of the sentinel lymph node in breast cancer?].

The sentinel lymph node procedure is now admitted by many teams for axillary evaluation in the early stage of breast cancer. The classical technique consists in an intraoperative examination of the sentinel lymph node under general anaesthesia during tumorectomy, deciding whether or not complete axillary lymphadenectomy must be done. Intraoperative examination seems to us to have a poor predictive value. In the case of a false positive, the surgeon would perform lymphadenectomy unnecessarily, while a false negative would mean that the patient would have to be re-operated for lymphadenectomy once the definitive results have become available. For all these reasons, we propose the detection of the sentinel lymph node under local anaesthesia and to await its definitive analysis before carrying out tumorectomy on the patient and axillary lymphadenectomy if necessary under general anesthesia. Hence, we consider that the best way to avoid the uncertainties of an intraoperative examination of the sentinel lymph node is not to carry out intraoperative examinations.

Axilla↗

PubMed2003

Evaluation of immunohistochemistry and multiple-level sectioning in sentinel lymph nodes from patients with breast cancer.

CONTEXT: Previous investigations on sentinel lymph node biopsies have demonstrated their importance in nodal staging of patients with breast cancer. However, sentinel node biopsy in breast cancer is currently a controversial procedure and continues to provoke debate. OBJECTIVES: We designed our study to determine the usefulness of a standard protocol for evaluating sentinel lymph node metastases and to assess the value of sentinel node biopsy as the only procedure in nodal staging in breast cancer patients. MATERIALS AND METHODS: A retrospective analysis of 84 breast cancer patients with sentinel node biopsies, who also underwent axillary dissection, was conducted using a standard protocol (3 levels of immunohistochemical stains for keratin and 2 levels of hematoxylin-eosin (HE) stains on the first 3 negative lymph nodes). RESULTS: Hematoxylin-eosin staining identified 20 patients (23.8%) with sentinel node metastases. The remaining 64 negative patients (76.1%) were tumor free on sentinel lymph nodes at level 1 HE. Additional immunohistochemical stains for keratin and HE stains on specimens from these 64 patients showed an additional 5 patients (7.8%) to be positive for lymph node micrometastases (<2 mm). The total percentage of cases with sentinel lymph node metastases detected by HE staining and immunohistochemistry was 29.7%. Of the remaining 59 cases that were negative on HE and immunohistochemistry, axillary dissection revealed 3 cases that had metastases in the axillary lymph nodes. The false-negative rate was 10.7%. The concordance rate between sentinel lymph nodes and axillary lymph nodes was 96.4%. The sensitivity was 89% and specificity was 100%. CONCLUSION: Immunohistochemistry and multiple-level sectioning increased detection of metastases by 7.8% in sentinel lymph nodes. Caution should be used in accepting sentinel node biopsy alone as the only procedure for staging due to a high false-negative rate (10.7%). A predictive value of 96.4% confirms that sentinel lymph node biopsy is most likely to contain metastatic carcinoma. Sentinel lymph node examination with the protocol we describe, combined with axillary dissection, increased the yield of metastatic disease by identifying 8 additional cases of nodal metastatic disease (an increase of 28%), as compared to standard axillary nodal dissection and single-section sentinel lymph node examination alone.

Adult↗

PubMedDate not supplied

Correlation of macroscopic and histological characteristics in the regional lymph nodes of patients with rectal and sigmoidal adenocarcinoma.

BACKGROUND/AIMS: The number of involved lymph nodes is a relevant prognostic parameter which determines the duration of survival in patients with colonic and rectal adenocarcinoma. The purpose of this study was to establish a correlation between the macroscopic (size and consistency) and microscopic characteristics of the regional lymph nodes (type of involvement in tumor tissue, state of the capsule, adherence of the lymph nodes, etc.) in patients with colorectal carcinoma. METHODOLOGY: In this prospective study, 46 patients with rectal and sigmoid adenocarcinoma were studied through randomized selection. From the resected specimens, a total of 736 lymph nodes were identified (average 15.66 per patient), with the precise location determined according to Enker and Philiphsken. The macroscopic and microscopic characteristics of each lymph node were identified. These lymph node findings were then distributed by means of the x2 test, while the interrelationship of lymph node characteristics was determined by factor analysis. RESULTS: Within the group of "small" lymph nodes, 17.18% were malignant. Additionally, of all the malignant lymph nodes, 46.23% were less than 5 mm in diameter. Although the malignant lymph nodes were predominantly diffusely involved within the tumor tissue, 19.50% were focally involved within the tumor tissue, of which 48.38% were "small" lymph nodes, which are commonly non-palpable. Perforation of the capsule and adherence were more characteristic for focally mutated than for diffusely mutated lymph nodes in the cases of malignantly mutated lymph nodes. CONCLUSION: Size and consistency of the lymph nodes are not dependable parameters for appraisal of lymph node involvement in tumor tissue, the state of the lymph node capsule, nor the interrelation among the lymph nodes. As in the case of the primary tumor, local tumor aggression in the lymph nodes is conditioned by the grade of differentiation, i.e. histologic immaturity, rather than by tumor size.

Adenocarcinoma↗