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Disparity in pathologic and clinical lymph node staging in oral tongue carcinoma. Implication for therapeutic decision making.

BACKGROUND: Regional lymph node metastasis is the most reliable predictor of treatment outcomes for patients with squamous cell carcinoma of the oral tongue (SCCOT). A recent American Joint Committee on Cancer staging update of malignant melanoma has incorporated pathologic lymph node staging. The authors hypothesized that pathologic lymph node staging (pN) would be a more reliable predictor of treatment outcomes than clinical lymph node staging (cN). METHODS: The authors retrospectively reviewed 266 patients who received primary surgical treatment for SCCOT, including a neck dissection, from January 1980 to December 1995. Overall and disease-specific survival and disease-free interval were compared with respect to clinical and pathologic lymph node stages. RESULTS: Statistically significant survival differences were identified for both clinical (cN0-cN2) and pathologic lymph node stages (pN0-pN2). However, survival and disease-free interval differences for pathologic lymph node staging reached higher statistical significance (P < 0.0001) than for clinical lymph node staging (P < 0.002). This disparity can be explained by stage migration (i.e., patients with cN0-1 disease have a more advanced lymph node stage at the time of pathologic review compared with patients without cN0-1 disease). The authors found a 34% rate of occult lymph node disease in the cN0 group (19% of occult lymph nodes had extracapsular spread [ECS]). Similarly, 43% of cN1 patients had a higher stage than pN2b disease and 50% had ECS. CONCLUSIONS: Pathologic lymph node staging, based on a staging or therapeutic neck dissection, should be considered for patients treated for SCCOT to identify high-risk patients who may benefit from additional adjuvant therapy. Prospective studies are essential to validate these findings before pathologic lymph node staging is included in standard staging criteria.

Carcinoma, Squamous Cell↗

Tritiated thymidine incorporation does not enhance sensitivity of the popliteal lymph node assay.

The popliteal lymph node (PLN) assay has been proposed as a tool to predict drugs and chemicals with the potential to induce systemic autoimmune reactions in man. In this assay, weight and cellularity indices typically are the measured endpoints. The present study was conducted to test whether incorporation of tritiated thymidine could improve sensitivity of the PLN assay. Male and female Balb/c mice were injected with 20 microCi of [3H]-methyl-thymidine intravenously 7 days after receiving 0.5, 1 or 2 mg of diphenylhydantoin, streptozotocin, sulfamethoxazole, ofloxacin, phenobarbital, or metformin intradermally. Results obtained with incorporation of tritiated thymidine were compared to weight indices. No consistent or marked differences in these endpoints were noted whatever the compound used. This study shows that incorporation of tritiated thymidine does not improve sensitivity of the PLN assay.

Animals↗

Magnetic resonance spectroscopy detects cancer in draining lymph nodes.

The spread of cancer cells to draining lymph nodes is an important prognostic factor for many cancers and influences postoperative therapy in patients. Histopathology is used routinely to assess if lymph nodes contain metastases. There are, however, time and resource constraints on the volume of lymph node tissue that can be examined by the pathologist in a routine laboratory (less than 2% of each node), thus major sampling errors are possible. Conventional histopathology also relies on identifying aggregates of malignant cells for a positive diagnosis. Proton (1H) magnetic resonance (MR) spectroscopy can detect chemical changes, specifically increased levels of lactate, choline, fucose and amino acids, in lymph nodes infiltrated by cancer. Increase in lactate indicates the presence of anaerobically respiring cells, whereas choline reports that the cells are replicating. Since MR spectroscopy can identify early infiltration by malignant cells, before cell clusters are visible under the light microscope, it detects micrometastases in lymph nodes missed histopathologically. Furthermore, MR spectroscopy eliminates sampling errors since the entire lymph node is examined.

Adenocarcinoma↗

Extracellular deposition of eosinophil granule major basic protein in lymph nodes of patients with Hodgkin's disease.

Lymph nodes from each of the four histologic types of Hodgkin's disease were examined for the presence of eosinophils and for eosinophil degranulation by immunofluorescent localization of eosinophil granule major basic protein (MBP). Eosinophil degranulation shown by MBP deposition outside of eosinophils was found in six of eight nodes from patients with nodular sclerosing disease and in two of eight nodes from patients with lymphocyte depletion-type disease. Three nodes of the mixed cellularity type, one node of the lymphocyte predominance type, and one lymph node of the lymphocyte depletion type showed one or two small foci of extracellular MBP deposition. Lymph nodes from patients without Hodgkin's disease showed no extracellular deposition of MBP. Large numbers of eosinophils were found in seven of eight nodes of the nodular sclerosing variant, but were less frequently seen among the other types of Hodgkin's disease. The presence of extracellular MBP in lymph nodes of patients with Hodgkin's disease indicates that eosinophil degranulation commonly occurs and suggests that the released eosinophil granule proteins may participate in the inflammatory reaction in this disorder more extensively than is presently appreciated.

Blood Proteins↗

Tumor size in endometrial cancer: a prognostic factor for lymph node metastasis.

The association of tumor size and lymph node metastasis in endometrial cancer clinically confined to the uterus was evaluated in 91 patients. Other factors possibly associated with lymph node metastasis were also analyzed. Tumor size was independently associated with lymph node metastasis when analyzed by multivariate analysis (P = .022). Patients with tumors less than or equal to 2 cm in diameter had only a 5.7% incidence of lymphatic metastases. When tumors exceeded 2 cm in diameter or involved the entire endometrial surface, metastases occurred in 21.7 and 40.0% of patients, respectively. Measuring tumor size at surgery, or possibly preoperatively by hysteroscopy, will help predict which patients are at increased risk for lymph node metastasis. There were no lymph node metastases in patients with tumors less than or equal to 2 cm in diameter and invasion of less than half of the myometrium. For these patients, extended surgical staging with pelvic and aortic lymph node biopsies may not be indicated.

Female↗

Incidence of metastases from rectal adenocarcinoma in small lymph nodes detected by a clearing technique.

The incidence of metastases from primary adenocarcinoma of the rectum in lymph nodes smaller than 5 mm is not known. Lymph nodes measuring less than or equal to 5 mm usually are not detected by manual techniques of examination of the surgical specimen. This retrospective analysis describes the results when a lymph node clearing technique that identifies lymph nodes as small as 1 mm was used to treat surgical specimens from 27 consecutive patients with rectal adenocarcinoma who underwent abdominoperineal resection with a curative intent and for whom all pathologic data were retrievable. Nine hundred thirty lymph nodes were found, with an average of 34 lymph nodes per specimen (range 0-88). Seventy-two of the 345 lymph nodes found in patients with Dukes C tumors were found to have metastases. Fifty-six (78 percent) of these 72 lymph node metastases occurred in lymph nodes measuring less than or equal to 5 mm. Three lymph node metastases were found in the perianal zone, 53 in the perirectal zone, and 16 in the pericolonic zone. Lymph node metastases from rectal adenocarcinomas often will occur in lymph nodes smaller than 5 mm. We concluded that the use of lymph node clearing techniques discovers these metastases, thereby offering the potential for enhanced staging of primary rectal adenocarcinomas.

Adenocarcinoma↗

Retroperitoneal lymph node resection in patients with cervical cancer.

OBJECTIVE: To determine predictive factors precluding complete resection of metastatic lymph nodes identified by pre-operative imaging in patients with cervical cancer. METHODS: Retrospective clinical review of patients with cervical cancer with suspected metastases to pelvic and/or periaortic lymph nodes who underwent lymph node dissection by laparotomy at The University of Texas M.D. Anderson Cancer Center from September 1990-December 2004. RESULTS: A total of 104 patients were the subject of this analysis. Post-operatively, 25 patients (24%) had negative lymph nodes, 62 patients (60%) had macroscopically positive lymph nodes, one patient had microscopically positive (1%) and 16 patients (15%) had unresectable lymph nodes. Body mass index did not have any impact on successful resection of lymph nodes. On univariate analysis age (p=0.049) and size and location of the largest lymph node were associated with resection status (p=0.001 and 0.020). Logistic regression confirmed that chance of achieving a successful resection decreases with increasing age (p=0.046) and size of largest lymph node (0.002). CONCLUSIONS: The ability to completely resect suspected metastatic lymph nodes at the time of extraperitoneal lymph node dissection in patients with cervical cancer is associated with size and location of largest lymph node.

Adult↗

Membrane-type 1 matrix metalloproteinase enhances lymph node metastasis of gastric cancer.

The mechanisms of the lymph node metastasis remain unclear. We demonstrate the role of MT1-MMP on the lymph node metastasis using in vivo experimental model of lymph node metastasis by orthotopic implantation of MT1-MMP transfected gastric cancer cell line in the stomach of nude rats. TMK-1 cell line without expression of MT1-MMP was transfected with the pcDNA3 plasmid containing a 3.4-kb MT1-MMP cDNA fragment by calcium phosphate method, and the transfected cell line was designated as TMK-MT. Western blot and RT-PCR analyses showed the specific bands corresponding to MT1-MMP in the TMK-MT cells. By gelatin zymography, the activated form (62-kDa) of MMP-2 was identified in the medium of TMK-MT cell line, but was not detected in TMK-1 cells. Six weeks after orthotopic implantation of TMK-1 and TMK-MT xenografts of nude mouse-subcutaneus tumor into the stomach of nude rats, gastric tumors were found in all the animals. Histologically, the lymphatic invasion was found in the submucosa of the TMK-MT gastric tumors. Lymph node metastasis was not detected in nude rats bearing TMK-1 gastric tumor (0/8). In contrast, lymph node metastasis was detected in five out of 8 rats, bearing TMK-MT gastric tumor. MT1-MMP immunoreactivity was found on the cell membrane and cytoplasm of TMK-MT cells not only in the lymph node metastasis but also in the stomach tumor. These results suggest that MT1-MMP overexpression induced by transfection of its gene may promote lymph node metastasis of transformed cells.

Animals↗

[Clinical study of lymph node metastatic pattern of thoracic esophageal squamous carcinoma].

OBJECTIVE: To analyze the patterns of lymph node metastases of thoracic esophageal carcinoma and define the adequate range of lymph node dissection. METHODS: The clinical data of 217 patients with esophageal carcinoma undergoing radical surgical resection of the lymph nodes in three regions were retrospectively analyzed. RESULTS: Lymph node metastases were found in 136 of the 217 patients (62.6%) and skip metastases of the lymph nodes in 12 patients (5.5%). In 3 989 lymph nodes desected, metastases were identified in 454 lymph nodes (11.38%). The rates of lymph node metastasis were 31.7%, 21.2% and 12.1% in the neck, thoracic mediastinum and abdominal cavity, respectively, in upper thoracic esophageal carcinoma, 21.9%, 30.5% and 15.6% in middle thoracic carcinoma, and 9.75%, 12.7% and 34.5% in lower thoracic carcinoma. The degree of tumor differentiation, depth of tumor invasion and lymphatic vessel invasion were factors influencing lymph node metastases (P<0.05). CONCLUSION: Because of the upward, downward and skip metastasis of esophageal carcinoma cells to the lymph nodes, the operable patients with thoracic esophagus carcinoma should receive radical desection of the lymph nodes in the 3 regions to promote the patients' survival.

Adult↗

Significance of para-aortic lymph node dissection in advanced gastric cancer.

BACKGROUND/AIMS: Since surgical results in advanced gastric cancer remain poor and para-aortic lymph node dissection may contribute to survival, it is useful to determine the significance of para-aortic lymph node dissection. METHODOLOGY: Para-aortic lymph node dissection was provisionally indicated for patients with invasion depth deeper than the subserosal layer. Clinicopathologic variables were retrospectively analyzed using univariate analysis and multivariate analysis to predict para-aortic lymph node metastasis. Similarly, they were analyzed using univariate analysis and the Cox's proportional hazards regression model to estimate the prognostic factor in 120 patients who underwent para-aortic lymph node dissection. Surgical results and post-operative complications were compared between para-aortic lymph node dissection and D2 dissection. RESULTS: Univariate analysis revealed that the mean diameter, the degree of lymph node metastasis, and the invasion depth were significant predictors of para-aortic lymph node metastasis. Multivariate analysis showed that n2 was the only independent predictive factor as to para-aortic lymph node metastasis. Univariate analysis revealed tumor site, tumor diameter, lymph node metastasis, number of positive lymph nodes, INF, and stage were significantly associated with 5-year survival. The Cox's proportional hazards regression model showed that the number of positive lymph nodes and the number of positive para-aortic lymph nodes were independent prognostic factors. Patients with < or = 10 positive lymph nodes in any stage or < or = 3 positive para-aortic lymph nodes in stage IVb had significantly better surgical results. Surgical results for patients who underwent para-aortic lymph node dissection with n2 or invasion depth deeper than the exposed serosa were significantly higher than those in D2. As to post-operative complications, pancreatic fistula and respiratory complications were significantly frequent after para-aortic lymph node dissection. CONCLUSIONS: n2 is helpful in predicting para-aortic lymph node metastasis. Whereas, post-operative morbidity such as pancreatic fistula and respiratory complications after para-aortic lymph node dissection were significantly higher, they were controllable. Para-aortic lymph node dissection should be indicated in advanced gastric cancer patients in which lymph node metastasis is over n2 or invasion depth is deeper than the exposed serosa. But the number of positive para-aortic lymph nodes must be less than three.

Aorta↗

Squamous cell carcinoma of the skin associated with sarcoid reactions in the regional lymph nodes.

Sarcoid reactions in lymph nodes with or without metastasis from a primary malignant neoplasm are well-known. However, it is extremely rare to find these reactions associated with cutaneous solid tumors; only one such case has appeared in the literature. Here we describe a case of an 83-year-old man with cutaneous squamous cell carcinoma accompanied by sarcoid reactions and metastatic foci in the regional lymph nodes. The possibilities of systemic sarcoidosis and tuberculosis were excluded after extensive examinations specific for these diseases. Some authors regard the sarcoid reaction to be a sign of a good prognosis on the basis of studies of a few patients with solid tumors. In our case, however, the patient died of pulmonary metastasis with pleuritis carcinomatosa shortly after surgery. Systematic analysis of a sufficient number of cases should be carried out to evaluate the clinical significance of this type of reaction.

Aged↗

[In situ mammary duct carcinoma with microinvasion. Which axillary lymph node exploration?].

OBJECTIVE: Specify the role of axillary lymph node removal in micro-invasive in situ duct carcinomas (DCIS-MI) of the breast with a series of 107 consecutive cases. METHODS: Single-centre, retrospective, anatomoclinical study with application of the European guidelines adopting as pathological definition the presence of areas of micro-invasion not exceeding 1mm. Axillary lymph node dissection was systematically complete and was preceded by the search for the sentinel node in 10 patients using the isotope method. RESULTS: Lymph node invasion was revealed in 8 cases in the global population (7.5%). All the cases except one exhibited typical deleterious histological features: comedo architectural sub-type, high nuclear grade, and size of the lesion>3 cm. The lymph node invasion was of 18.5% in the sub-group of high-grade micro-invasive comedo-carcinomas measuring more than 3 cm. CONCLUSION: Contrary to those exhibiting pure DCIS, DCIS-MI patients require surgical exploration of the armpit, the most appropriate modalities of which are currently debated: classical axillary lymph node dissection or search for the sentinel lymph node; the selective lymphadenectomy procedure is not yet a consensually validated technique.

Adult↗

Histopathological features of occult metastasis detected by sentinel lymph node biopsy in oral and oropharyngeal squamous cell carcinoma.

OBJECTIVES: Sentinel lymph node biopsy has been introduced for head and neck cancer with promising results. Research in breast cancer has revealed different histopathological features of occult lymph node metastasis with possibly different clinical and prognostic implications. The aim of the study was to evaluate the histopathological features of occult metastasis detected by sentinel lymph node in oral and oropharyngeal squamous cell carcinoma. STUDY DESIGN: Prospective. METHODS: According to Hermanek (5), occult metastasis was differentiated into isolated tumor cells and infiltration of lymph node parenchyma smaller than 2 mm in diameter (micrometastasis) and larger than 2 mm in diameter (metastasis). RESULTS: Occult metastases were found in 6 of 19 (32%) sentinel lymph nodes. Three patients showed micrometastasis with a mean size of 1.4 mm (range, 1.2-1.5 mm), the first with three separate micrometastases within the same sentinel lymph node, the second with an additional cluster of isolated tumor cells within the same sentinel lymph node, and the third with an additional micrometastasis in one lymph node of the elective neck dissection. Two patients had macrometastasis (3.4 and 8 mm), both with multiple metastases in the elective neck dissection. One patient had two clusters of isolated tumor cells in the sentinel lymph node and an additional cluster of isolated tumor cells in one lymph node of the elective neck dissection. CONCLUSIONS: Occult metastasis can be subdivided histopathologically in isolated tumor cells, micrometastasis, and macrometastasis. We present the first study describing a great variety of these subtypes in sentinel lymph nodes from head and neck squamous cell carcinoma. Because the independent prognostic factor and clinical relevance of these subtypes is still unclear, we emphasize the importance of reporting these findings uniformly and according to well-established criteria.

Adult↗

[Significance of detection of micrometastases in regional lymph nodes in cancer patients using RT-PCR].

Lymph node metastasis is the most important predictor of prognosis, and lymph node dissection is indispensable in achieving curative resection. However, even in patients who undergo curative resection, 20-30% experience relapse, which may be due to micrometastases that are undetectable by conventional histologic methods. Recently, more specific and sensitive genetic methods, including the reverse-transcriptase polymerase chain reaction (RT-PCR), have been introduced to detect micrometastases. We review the literature to evaluate the significance of detecting micrometastases in lymph nodes by RT-PCR. Since the first study by Smith in 1991, many authors have reported molecular diagnoses in the lymph nodes, blood, and bone marrow in patients with various types of cancer using markers such as CEA and cytokeratins. Many researchers have found RT-PCR to be more sensitive than conventional histological methods in detecting lymph node metastases. Molecular diagnosis will become a powerful tool for predicting prognosis and determining who should receive postoperative adjuvant chemotherapy. However, reports on the relationship between molecular diagnosis and prognosis are still few. It will be important to clarify this relationship in large-scale clinical trials to evaluate the significance of detecting micrometastases in the lymph nodes.

Biomarkers, Tumor↗

[Cavitating mesenteric lymph node syndrome].

Cavitating mesenteric lymph node syndrome (CMLNS) is a complication of celiac disease (chronic enteropathy characterized by intolerance to gluten ingestion) that is documented but poorly understood. Patients with CMLNS often present with weight loss that is refractory to treatment, fatigue, and diarrhea associated to clinical signs and laboratory findings of hyposplenism. Computed tomography shows multiple cystic mesenteric masses with a central low attenuation area caused by the presence of fluid and/or adipose material in the central cavity of the mesenteric lymph node.

Celiac Disease↗

Genetic diagnosis of lymph-node metastasis in colorectal cancer.

If a regional lymph node taken during surgery for colorectal cancer is found to be free of tumour on histological examination this is taken to be a good sign. However, conventional staining may not be sensitive enough. Mutant-allele-specific amplification (MASA) is a technique that can detect, at the level of an individual cell, micrometastases to lymph nodes that are histologically diagnosed as negative. To examine the prognostic significance of such genetically detectable tumour cells we screened 120 colorectal cancers from patients who had no histologically detectable lymph-node metastasis at the time of surgery for mutations in K-ras (codons 12, 13, and 61) or p53 (exons 5-8). Somatic mutations were identified by MASA in 71 tumours. We next examined preserved tissues from corresponding regional lymph nodes, using MASA to look for the specific mutation found in the primary. Of 37 patients with genetically positive lymph nodes 27 had had a tumour recurrence within 5 years of surgery; none of the 34 patients who were MASA negative for lymph node metastasis had had a recurrence. Genetic diagnosis of lymph node metastasis may be a useful prognostic factor in colorectal cancer, and it could also serve as a selective marker for intensive postoperative adjuvant chemotherapy.

Colorectal Neoplasms↗

Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with Stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy.

BACKGROUND: The incidence and distribution pattern of retroperitoneal lymph node metastasis in patients with cervical carcinoma should be investigated based on data from systematic pelvic lymph node (PLN) and paraaortic lymph node (PAN) dissection, so that a basis can be established for determining the site of selective lymph node dissection or sampling. METHODS: A total of 208 patients with Stages IB, IIA, and IIB cervical carcinoma who underwent radical hysterectomy and systematic pelvic and PAN dissection were investigated for lymph node metastasis and histopathologic risk factors for lymph node metastasis. RESULTS: Fifty-three patients (25.5%) had lymph node metastasis. The obturator lymph nodes were most frequently involved, with a rate of 18.8% (39/208). Forty-nine of 53 node-positive patients had lymph node metastasis in the obturator, internal iliac, or common iliac lymph nodes. Of 26 solitary lymph node metastases confined to one node group, 18 were in the obturator, 3 in the internal iliac, 3 in the parametrial, and 2 in the common iliac lymph nodes. A multiple logistic regression analysis revealed that deep cervical stromal invasion and lymph-vascular space invasion were related to PLN metastasis. It was also shown that metastasis to bilateral PLNs (excluding the common iliac lymph nodes) as well as metastasis to the common iliac lymph nodes were significantly related to PAN metastasis. CONCLUSIONS: The results of this study suggest that the obturator lymph nodes can be sentinel lymph nodes of cervical carcinoma. PAN metastasis appears to occur secondarily to wide-spread PLN metastasis. These results provide a basis for determining the site of selective lymph node dissection and for estimating the existence of PAN metastasis from the pattern of metastasis in PLN in patients with cervical carcinoma.

Adult↗

Establishment of an oral squamous cell carcinoma cell line with high invasive and p27 degradation activities from a lymph node metastasis.

The extent of lymph node metastasis is a major determinant in the prognosis of oral squamous cell carcinoma (OSCC). We present here a new OSCC cell line, MSCC-1, established from a lymph node metastasis of a patient with OSCC of gingiva. First, we examined the expression of p27, p53 and Ki-67 in non-neoplastic mucosa, primary and metastatic cancer lesions by immunohistochemistry. Metastatic cancer cells in the lymph node showed the reduced expression of p27 in comparison with cancer cells in the primary lesion. Cancer celLs both in the primary and metastatic lesions showed overexpression of p53 and Ki-67. Overexpression of p53 and reduced expression of p27 in MSCC-1 cells were also determined by western blot analysis. To characterize MSCC-1 cells, furthermore, we examined the invasive activity and cell proliferation of MSCC-1, comparing with those of other OSCC cell lines, HSC-2 and HSC-3 cells. The invasive capacity of MSCC-1 cells was significant higher than HSC-2 and HSC-3 cells, but cell growth of MSCC-1 cells was slower than HSC-2 and HSC-3 cells. Moreover, we examined the p27 degradation activity by in vitro degradation assay. Interestingly, MSCC-1 cells have the strongest p27 degradation activity among the OSCC cell lines examined. In the present study, we newly established MSCC-1 cells with strong invasiveness and p27 degradation activity from a metastatic lesion. These findings suggest that high activity of p27 degradation may concern with invasiveness of OSCC cells and that MSCC-1 cells can be a useful cell model for studying the detailed mechanism of p27 degradation, invasion and metastasis of OSCC.

Blotting, Western↗