The prognostic significance of the percentage of positive/dissected axillary lymph nodes in breast cancer recurrence and survival in patients with one to three positive axillary lymph nodes

BACKGROUND: Adjuvant therapy for women with T1-T2 breast carcinoma and 1-3 positive lymph nodes is controversial due to discrepancies in reported baseline locoregional recurrence (LRR) risks. This inconsistency has been attributed to variations in lymph node staging techniques, which have yielded different numbers of dissected lymph nodes. The current study evaluated the prognostic impact of the percentage of positive/dissected lymph nodes on recurrence and survival in women with one to three positive lymph nodes. METHODS: The study cohort was comprised of 542 women with pathologic T1-T2 breast carcinoma who had 1-3 positive lymph nodes and who had undergone mastectomy and received adjuvant systemic therapy without radiotherapy. Ten-year Kaplan-Meier (KM) LRR, distant recurrence (DR), and overall survival (OS) rates stratified by the number of positive lymph nodes, the number of dissected lymph nodes, and the percentage of positive lymph nodes were examined using different cut-off levels. Multivariate analysis was performed to evaluate the prognostic significance of the percentage of positive lymph nodes in disease recurrence and survival. RESULTS: The median follow-up was 7.5 years. LRR, DR, and OS rates correlated significantly with the number of positive lymph nodes and the percentage of positive lymph nodes, but not with the number of dissected lymph nodes. The cut-off level at which the most significant difference in LRR was observed was 25% positive lymph nodes (the 10-year KM LRR rates were 13.9% and 36.7% in women with < or = 25% and > 25% positive lymph nodes, respectively; P < 0.0001). Higher DR rates and lower OS rates were observed among patients who had > 25% positive lymph nodes compared with patients who had < or = 25% positive lymph nodes (DR: 53.0% vs. 30.3%, respectively; P < 0.0001; OS: 43.4% vs. 62.6%, respectively; P < 0.0001). In the multivariate analysis, the percentage of positive lymph nodes and the histologic grade were significant, independent factors associated with LRR, DR, and OS. CONCLUSIONS: The presence of > 25% positive lymph nodes was an adverse prognostic factor in patients with 1-3 positive nodes and may be used to identify patients at high risks of postmastectomy locoregional and distant recurrence who may benefit with adjuvant radiotherapy and more aggressive systemic therapy regimens.     

The role of surgery in the management of selected patients with small-cell carcinoma of the lung

This study was designed to evaluate the efficacy of surgical resection of the primary tumor and lymph nodes in patients with localized small-cell carcinoma who had responded to induction chemotherapy. The study was performed in 37 patients who received two cycles of chemotherapy consisting of cyclophosphamide, doxorubicin, and etoposide. Those patients who achieved a complete or partial (greater than 50%) response were evaluated for thoracotomy and the primary tumor and regional lymph nodes excised when feasible. Postoperatively, the patients received prophylactic cranial irradiation and were maintained on the same chemotherapy for an average of 11 months. Twelve patients were resected and found to have residual small-cell carcinoma in the operative specimen (ten) or no residual disease (two). Seven of these patients (58%) are alive without evidence of disease (median follow-up, 24 months). Seven other patients who were resected proved to have either residual foci or small-cell carcinoma mixed with adenocarcinoma or large-cell carcinoma (four) or only focal areas of adenocarcinoma, large-cell carcinoma, or squamous-cell carcinoma with no evidence of residual small-cell carcinoma. Five of these patients (71%) are alive without evidence of disease (median follow-up, 36 months). Two of the 16 patients who were not resected but treated with chemotherapy and radiation are alive at 15 and 31 months without evidence of disease, the other 14 are dead of disease.     

Lymphadenectomy in gastric cancer: influence on prognosis of lymph node count

To better understand the role of the number of lymph nodes retrieved on long-term outcome of gastric cancer treatment, 154 patients who had undergone curative resection, with dissection of >15 nodes were retrospectively studied. Dissection of perigastric and extraperigastric lymph nodes, defined as 'extended' (>26 nodes dissected) in 39 cases and 'limited' (< or = 26 nodes dissected) in 115 cases, was performed. A total of 3479 lymph nodes (mean 22.6 per specimen), were dissected and of these 721 showed metastases. A mean of 8.1 lymph node metastases, per metastatic case, was found. Regression analysis showed no independent factor associated with the extent of lymphadenectomy. Depth of wall invasion (p=0.000) and histological growth pattern (p=0.044) were independently associated with the number of lymph nodes involved (pN0, pN1 1-7, pN2 >7). The cumulative 5-year survival rate was 47% in patients without lymph node metastases; 29% in those with 1-7 nodes involved and 17% in those with >8 nodes involved (p=0.002). Receiver operating characteristic (ROC) curve analysis, in 65 nodenegative cancer cases, demonstrated an area under the curve for vital status (alive or dead) of 0.602 (95% CI: 0.473 - 0.721). All node-negative cases with a number equivalent to or exceeding the cutoff point of 23 nodes were alive. ROC analysis showed 11 to be the cutoff number of metastasized lymph nodes in correlation with vital status. Almost all those patients in whom the number of positive nodes was equivalent to, or exceeded the cutoff point had died (area under the ROC curve 0.633; 95% CI: 0.524 - 0.733). ROC analysis showed that the cutoff lymph node ratio, in relation to vital status, was 0.33. The majority of patients at or above this cutoff point had died (area under ROC curve 0.682; 95% CI: 0.574 - 0.776). Multivariate survival analysis showed that lymph node ratio was the only independent prognostic factor (p=0.001). The present findings suggest that, in lymphadenectomy with at least 15 nodes, the number and status of regional nodes dissected, irrespective of the location, provide reliable prognostic information on curatively resected gastric carcinomas.     

Primary splenic presentation of malignant lymphoma and related disorders. A study of 49 cases

The diagnosis of malignant lymphoma presenting as an initial splenic manifestation may go unrecognized as such when peripheral lymph nodes are not enlarged and when results of bone marrow biopsies are negative. Tissues from 49 patients, ranging in age from 15 to 78 years, in whom the original diagnosis of malignant lymphoma and related conditions was made at splenectomy, were classified as: diffuse small lymphocytic (20), diffuse large cell (11), diffuse small cleaved (5), diffuse large cell, immunoblastic (5), follicular small cleaved cell (3), and follicular mixed small cell and large cell (2). Two additional spleens, diagnosed as acute blastic leukemia, were initially confused with malignant non-Hodgkin's lymphoma by light microscopy. One patient presented with Hodgkin's disease confined to the spleen. For the non-Hodgkin's lymphoma group, parameters of age, sex, splenic weight (range, 226-4000 g), lymph node, bone marrow, or liver involvement did not adversely influence prognosis. Abdominal lymph nodes were positive in 31 of 37 patients having splenic hilar and/or abdominal lymph nodes available for review. Of 29 patients with adequate follow-up, 7 died of disease, 5 were free of disease at 3 years, 2 were free of disease at 5 years, 2 were alive with disease at 3 years, 4 were alive with disease at 5 years, and 9 died from second malignancies, unknown, or unrelated causes. Six of the 7 patients who died of lymphoma were classified as large cell (four diffuse large cell and two diffuse large cell, immunoblastic), with a mean 2-year survival. One patient died of leukemia. Those lymphomas classified as low grade behaved in an indolent fashion. The morphologic diversity of these cases emphasizes the need for the initial recognition and correct classification of lymphomas which present in the spleen, since survival is best determined according to histologic type.     

Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status

BACKGROUND: The current TNM classification system does not consider tumor length or the number of lymph nodes in the staging and classification scheme for patients with esophageal carcinoma. Using data from the National Cancer Institute SEER Program, the authors explored the effect of tumor length and number of positive lymph nodes on survival in patients with esophageal carcinoma. METHODS: Patients with esophageal adenocarcinoma or squamous cell carcinoma were subgrouped according to historic stage with localized, regional, or distant disease. Demographic factors (age at diagnosis, race, and gender) and tumor characteristics (morphology, histologic grade, tumor length, primary site, depth of invasion, number of positive lymph nodes, proportion of positive lymph nodes dissected, and distant metastatic sites) were examined. RESULTS: Overall factors that were associated with an increased mortality risk included increasing age at diagnosis, black race versus white race, histologic grade, primary tumor site in the lower esophagus and abdomen versus upper regions, and increasing depth of invasion. Among patients with regional disease, the number of positive lymph nodes (>/= 5 vs. < 5) was related to an increasing risk (hazard ratio [HR], 1.29; 95% confidence interval [95%CI], 1.06-1.56). The proportion of positive lymph nodes compared with the number of lymph nodes dissected conferred an increased risk (HR, 1.63; 95%CI, 1.26-2.11). Among patients with distant disease, sites other than distant lymph nodes implied an increased mortality risk (HR, 1.37; 95%CI, 1.37-1.65). Tumor length was an independent predictor of mortality when controlling for depth of invasion in patients with localized disease (HR, 1.15; 95%CI, 1.08-1.21). CONCLUSIONS: Tumor length, the number of involved lymph nodes, and the ratio of positive lymph nodes are important prognostic factors for survival in patients with esophageal carcinoma. A revised TNM classification system for patients with esophageal carcinoma might consider adding tumor length and number of positive lymph nodes as two important prognostic factors.     

Sentinel node detection in breast carcinoma

AIMS AND BACKGROUND: The standard procedure for the evaluation of axillary nodal involvement in patients with breast cancer is still complete lymph node dissection. However, about 70% of patients are found to be free of metastatic disease while axillary node dissection may cause significant morbidity. Lymphatic mapping and sentinel lymph node (SLN) biopsy are changing this situation. METHODS AND STUDY DESIGN: In a period of 18 months we studied 201 patients with breast cancer, excluding patients with palpable axillary nodes, tumors > 2.5 cm in diameter, multifocal or multicentric cancer, pregnant patients and patients over 80 years of age. Before surgery 99mTc-labeled colloid and vital blue dye were injected into the breast to identify the SLN. In lymph nodes dissected during surgery the metastatic status was examined by sections at reduced intervals. Only patients with SLNs that were histologically positive for metastases underwent axillary dissection. RESULTS: We localized one or more SLNs in 194 of 201 (96.5%) patients; when both techniques were utilized the success rate was 100%. Histologically, 21% of patient showed SLN metastases (7.8% micrometastases) and 68% of these had metastases also in other axillary nodes. None of the patients with negative SLNs developed metastases during follow-up. CONCLUSIONS: At present there is no definite evidence that negative SLN biopsy is invariably correlated with negative axillary status; however, our study and those of others demonstrate that SLN biopsy is an accurate method of axillary staging.     

RT-PCR法检测MUC1 mRNA诊断肺癌纵隔淋巴结隐匿转移

目的：探讨对常规病理检查漏诊的肺癌纵隔淋巴结转移病灶的诊断方法。方法：应用逆转录聚合酶链反应法（RT－PCR），检测pN0.1期非小细胞肺癌患者（NSCLC）纵隔淋巴结中MUC1基因mRNA的表达。结果：5枚肺良性疾病的局部淋巴结无MUC1基因mRNA表达，5枚经病理检查证实有淋巴结转移癌的NSCLC纵隔淋巴结中均检测中MUC1mRNA表达，实验组19例患者的78例枚纵隔淋巴结中有6枚检测到MUC1mRNA表达，从而诊断为纵隔淋巴结隐匿转移。结论：应用RT－PCR法检测纵隔淋巴结中MUC1基因mRNA的表达可以提高临床对肺癌纵隔淋巴结转移诊断的准确性。     

Squamous cell carcinoma of the tonsils: a molecular analysis of HPV associations.

BACKGROUND: The role of human papilloma virus (HPV) in the pathogenesis and biological behavior of tonsillar squamous cell carcinoma (TSCC) are areas of intense investigation. METHODS: This study used PCR analysis to identify HPV in paraffin-embedded tonsillar and nodal tissue from 52 patients with TSCC and 48 age (+/-5 year)/gender-matched controls with benign tonsillar hyperplasia. Results were correlated with HLA-DRB1 haplotype and clinical outcome. RESULTS: HPV was identified in 46% of patients with TSCC and 6% of controls. DNA sequencing showed the presence of HPV type 16 in 21 patients (40%) with TSCC. There was no statistically significant association between HLA-DRB1 expression and TSCC or HPV infection. Fifteen of 16 patients with HPV-positive TSCC with regional metastases had evidence of HPV in pathologically involved lymph nodes. In eight HPV 16-positive TSCC patients with lymph node metastasis, PCR testing identified HPV 16 in 17 of 23 histologically negative lymph nodes. Patients with HPV-positive TSCC without metastatic disease had no evidence of HPV in their lymphatic tissue. Clinically, HPV-associated carcinoma was present in younger patients in comparison with HPV-negative TSCC patients (mean age, 56.6 versus 66 years; P = 0.001). The odds for patients with HPV infection to develop TSCC were 18.2 times greater than for patients without HPV infection (95% confidence interval 4.6, 73.1). There was no statistically significant association between presence of HPV and cause-specific survival (hazard ratio = 2.5 for HPV negative versus positive; P = 0.26), after adjusting for age in a Cox proportional hazards regression analysis. CONCLUSION: HPV is an independent risk factor for TSCC. Identification of HPV in the histologically positive and negative lymph nodes of patients with HPV-positive TSCC/metastatic disease supports the role of HPV in the oncogenesis of TSCC.     

Effect of Neoadjuvant Chemotherapy on Axillary Lymph Node Positivity and Numbers in Breast Cancer Cases

Background: The aim of this study is to compare the numbers of axillary lymph nodes (ALN) taken out by dissection between patients with breast cancer operated on after having neoadjuvant chemotherapy (NAC) treatment and otherswithout having neoadjuvant chemotherapy, and to investigate factors affecting lymph node positivity. Materials and Methods: A total of 49 patients operated due to advanced breast cancer after neoadjuvant chemotherapy and 144 patients with a similar stage of the cancer having primary surgical treatment without chemotherapy at the general surgery clinic of Ondokuz Mayis University Medicine Faculty between the dates 01.01.2006 and 31.10.2012 were included in the study. The total number of lymph nodes taken out by axillary dissection (ALND) was categorized as the number of positive lymph nodes and divided into variables to be compared were analysed using the program SPSS 15.0 with PResults: Median number of dissected lymph nodes from the patient group having neoadjuvant chemotherapy was 16 (16-33) while it was 20 (5-55) without chemotherapy. The respective median numbers of positive lymph nodes were 5 ( 0-19) and 10 (0-51). In 8 out of 49 neoadjuvant chemotherapy patients (16.3%), the number of dissected lymph nodes was below 10, and it was below 10 in 17 out of 144 primary surgery patients. Differences in numbers of dissected total and positive lymph nodes between two groups were significant, but this was not the case for numbers of breast cancer having neoadjuvant chemotherapy may be less than without chemotherapy. This may not always be attributed to an inadequate axillary dissection. More research to evaluate the numbers of positive lymph nodes are required in order to increase the reliability of staging in the patients with breast cancer undergoing neoadjuvant chemotherapy.     

Adjuvant dose-intense chemotherapy with peripheral blood stem cell support in stage II-III breast cancer with five to nine involved axillary lymph nodes

The purpose of this study is to determine outcomes for patients with high-risk nonmetastatic breast cancer undergoing high-dose chemotherapy with peripheral blood stem cell support. Forty-three patients with stage II-III disease, five to nine positive axillary lymph nodes, and a median age of 44 years (range, 27-60 years) were enrolled in a study that included: 1) standard dose doxorubicin, 5-fluorouracil, and methotrexate adjuvant therapy; 2) cyclophosphamide, etoposide, filgrastim, and peripheral blood stem cell harvest; and 3) high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by peripheral blood stem cell infusion. All 43 patients received doxorubicin, 5-fluorouracil, and methotrexate, 42 (98%) received etoposide, and 41 (95%) received CTCb. Thirty-two patients (74%) are alive, 28 (65%) without relapse at a median of 55 months (range, 41-87 months). Two died (5%) of treatment-related causes, (subclavian catheter complication after etoposide and late radiation pneumonitis), and nine other deaths (21%) were associated with recurrent breast cancer. The probabilities of overall and event-free survival at 4 years were 0.77 and 0.67, respectively, compared with 0.82 and 0.69, respectively, for 72 similar patients with 10 or more positive axillary nodes receiving the same sequence of therapy. Thus, patients with five to nine positive axillary lymph nodes have a similar risk of failure after high-dose chemotherapy and peripheral blood stem cell support as patients with 10 or more positive axillary lymph nodes.     

胸段食管鳞状细胞癌淋巴结转移、肿瘤长度与预后的关系

 目的　分析胸段食管鳞状细胞癌（简称食管癌）淋巴结转移的数量及其转移度、肿瘤长度与预后的关系。方法　对1995年7月至2005年7月胸段食管癌根治术后患者526例,采用SPSS 13.0软件对临床资料进行统计学生存分析。结果　淋巴结转移数量＞3个者预后不良; 淋巴结转移度＞20 %者预后不良;肿瘤长度分3组（≤5 cm、5 cm＜长度＜7 cm、＞7 cm）,各组1、3、5、10年生存率（84.44 %、47.79 %、36.90 %、35.52 %;73.51 %、40.29 %、23.87 %、20.64 %;64.44 %、13.92 %、0、0）比较差异有统计学意义（P＝0.001）。结论　胸段食管癌淋巴结转移数量、转移度及肿瘤长度与预后有重要关系,能反映其预后,建议pTNM分期将淋巴结转移数考虑在内。     

Prognostic value of the number of involved nodes after neck dissection in oropharyngeal and oral cavity carcinoma]

PURPOSE: To evaluate the relationship between the number of positive nodes and probabilities of locoregional control and survival in patients with invasive squamous cell carcinomas of the oral cavity and oropharynx. MATERIAL AND METHODS: Between 1976 and 1993, we treated with curative intent 183 patients (median age: 56 years; standard deviation: 10 years). Seventy-nine patients (43%) had oropharyngeal primary invasive carcinoma and 104 (57%) had oral cavity (excluding the lip) primary invasive carcinoma. Patients with simultaneous primary lesion or visceral metastases were excluded from the analysis. All the patients had neck dissection with at least six nodes to analyse. One-hundred fifty-nine patients (87%) underwent resection of the primary lesion and 158 (86%) were treated postoperatively with external beam irradiation alone or combined with interstitial implant (median dose: 60 Gy; standard deviation: 10 Gy). Average follow-up was 52 months. RESULTS: The overall 5-year survival rate using the Kaplan-Meier method was 42.6%. The 5-year survival rates were 60.0% when lymph nodes were histologically negative, 39.5% when one lymph node was positive, 28.0% when two lymph nodes were positive and 24.4% when three or more lymph nodes were positive (P = 0.0004). The number of positive nodes did not significantly influence the specific disease-free survival and locoregional control rates. CONCLUSION: Patients with one or more positive neck nodes must have postoperative treatment.     

The impact of breast cancer screening on survival. A 5- to 10-year follow-up study

The Missouri Breast Cancer Detection Demonstration Project (BCDDP) at the Cancer Research Center in Columbia, Missouri, detected 136 malignant lesions among 10,187 asymptomatic participants between 1974 and 1980. Mammography was the sole detection modality in 76 or 56% of cases (Group 1). Mammography combined with physical examination revealed 41 (30%) additional cases (Group 2). Physical examination alone detected 19 (14%) cases (Group 3). Follow-up was complete in all cases. There were 26 (19%) noninvasive and 110 (81%) invasive lesions. Positive axillary nodes were found in 34 (25%) cases, and 102 (75%) patients had negative nodes. The overall 5-year survival was 84.5%. After a minimum follow-up of 5 years and a median follow-up of 8.5 years, 108 patients are alive, 5 of whom have recurrences. Among 28 deceased patients, 9 died of causes unrelated to breast cancer. The 5-year survival of Group 1 was 95% (72/76). Among this group of patients, 84% (64/76) had negative lymph nodes. At 5 to 10 years follow-up, there have been no breast cancer-related deaths among this group, and only one patient has recurrent disease 91 months after mastectomy. Furthermore, 85% (22/26) of all noninvasive lesions were found in this group. Of the remaining 12 patients diagnosed by mammography alone but who had positive nodes, the 5-year survival was 75% (9/12). By contrast, patients diagnosed by mammography plus physical examination (Group 2) experienced a survival of 71% (29/41) at 5 years. Sixty-three percent of patients diagnosed by physical examination had negative lymph nodes. Their 5-year survival was 84%, which contrasts with a 50% 5-year survival for patients with positive nodes. In Group 3, 79% (15/19) had negative nodes. The 5-year survival rate of this group was 74% (14/19), and the 5-year survival rate of the node-negative patients with invasive disease in this group was 29% and 21% lower than that of the node-negative patients with invasive disease of Groups 1 and 2, respectively (P less than 0.01). This study suggests that improved survival in breast cancer screening program is in large measure dependent on the ability to detect lesions before they become palpable. The authors conclude that mammography is a determining factor in early diagnosis, and at 5 to 10 years contributes significantly to improved 5- and 10-year survival rates.     

子宫内膜癌腹膜后淋巴结多点活检的临床意义

目的:探讨子宫内膜癌腹膜后淋巴结多点活检的临床意义.方法:对本院1990年1月～2000年12月初次手术时行腹膜后淋巴结活检的165例子宫内膜癌患者进行回顾性分析.比较各种临床病理因素的腹膜后淋巴结转移率,淋巴结转移与无转移及不同转移数目的5年生存率.结果:165例腹膜后淋巴结多点活检中,21例病理证实淋巴结转移,5年生存率23.81%,中位生存期30.20个月,与无淋巴结转移107例(随访5年以上),5年生存率66.36%,中位生存77.30个月,两者比较(P＜0.001).淋巴结转移≤3枚10例,5年生存率50.00%,中位生存42.10个月与淋巴结转移≥4枚11例,无5年生存,中位生存期21.30个月,两者相比(P＜0.001).经单因素分析,临床分期、组织类型、病理分级、肌层浸润深度、宫颈浸润、宫旁浸润及附件浸润、淋巴血管瘤栓与腹膜后淋巴结转移有关(P＜0.05),经多因素相关分析,此8个变量间比较,差异有显著性(P＜0.05).结论:腹膜后淋巴结多点活检能使手术病理分期更准确,是子宫内膜癌预后的重要因素之一,临床Ⅰ、Ⅱ期子宫内膜癌手术应常规行腹膜后淋巴结多点活检.     

Sentinel lymph node navigation surgery for pancreatic head cancers

Recently, sentinel lymph node (SN) concept has been validated for gastrointestinal and breast cancers. Our previous study has shown that the No. 13 posterior pancreaticoduodenal lymph node group constitutes the major regional drainage site from primary tumors in the pancreatic head, and that the status of these nodes predicts that of the No. 16 abdominal paraaortic lymph node group. Based on these results, we have developed SN navigation surgery for pancreatic cancer, in the search for more curable and less invasive surgery. In brief, 2% patent blue dye is injected into the peritumoral area. Approximately 5 min later, one or more blue-stained nodes within the area of the No. 13 lymph node group are identified and excised for intraoperative frozen section examination. The subsequent surgical decision-tree is as follows: i) if No. 13 SNs are negative, an extended No. 16 lymph node dissection is not performed to reduce morbidity, and ii) when cancer is found, the No. 16 lymph nodes are dissected completely. Since July 1997, nine of 21 patients scheduled to undergo an extended curative surgery underwent SN biopsy. SNs within the area of the No. 13 lymph node group were identified in 8 (89%) patients. An extended No. 16 lymph node dissection was avoided in 4 SN-negative patients. The overall 3-year survival rate of the 21 patients was 36%, and 4 patients (three SN-negative and one SN-positive patients) with stage IVa disease were alive 3 years after surgery. Three SN-negative patients underwent an extended curative pylorus-preserving pancreaticoduodenectomy (PpPD) with combined portal vein resection, but without an extended No. 16 dissection. In conclusion, SN biopsy and curative PpPD can increase curability, reduce morbidity, and provide long-term survival in patients with locally advanced pancreatic head cancer as an alternative to routine extended No. 16 lymph node dissection.     

Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence.

Disseminated disease, especially to the liver, constitutes the major risk of recurrence for colorectal cancer patients. However, successful resection can still be achieved in 25-35% of colorectal cancer patients with isolated metastases. To evaluate the clinical value of occult micrometastatic disease detection in lymph nodes, we tested genetic (K-ras and p53 gene mutations) and epigenetic (p16 promoter hypermethylation) molecular markers in the perihepatic lymph nodes from colorectal cancer patients with isolated liver metastases. DNA was extracted from 21 paraffin-embedded liver metastases and 80 lymph nodes from 21 colorectal cancer patients. K-ras and p53 gene mutations were identified in DNA from liver metastases by PCR amplification followed by cycle sequencing. A sensitive oligonucleotide-mediated mismatch ligation assay was used to search for the presence of K-ras and p53 mutations to detect occult disease in 68 lymph nodes from tumors positive for these gene mutations. Promoter hypermethylation at the p16 tumor suppressor gene was examined in both liver lesions and lymph nodes by methylation-specific PCR. Sixteen of the 21 (76%) liver metastases harbored either gene point mutations or p16 promoter hypermethylation. Twelve of the 68 lymph nodes were positive for tumor cells by molecular evaluation and negative for tumor cells by histopathology and cytokeratin immunohistochemistry, whereas none were positive for tumor cells by histopathology or negative for tumor cells by molecular analysis (P = 0.0005, McNemar's test). Moreover, in three patients with lymph nodes that were histologically negative at all sites, molecular screening detected tumor DNA at one or more lymph nodes. Survival analysis showed a median survival of 1056 days for patients without evidence of lymph node involvement by molecular analysis and 165 days for patients with positive lymph nodes by this approach (P = 0.0005). These results indicate that lymph node metastasis screening in colorectal cancer patients by molecular-based techniques increases the sensitivity of tumor cell detection and can be a good predictor of recurrence in colorectal cancer patients with resectable liver metastases.     

Immunohistochemical demonstration of cytokeratin is useful for detecting micrometastatic foci from gallbladder carcinoma in regional lymph nodes

BACKGROUND: The histological detection of lymph node metastasis in patients with gallbladder carcinoma is of major prognostic significance. However, it may be difficult to identify nodal involvement by conventional pathological examination of hematoxylin-eosin (HE)-stained sections when metastases are of microscopic size. In the present study, an attempt was made to detect lymph node metastasis precisely from gallbladder carcinoma, even by low-power microscopic examination, using immunohistochemistry with an anti-cytokeratin antibody. METHODS: A total of 431 lymph node specimens dissected during surgery from 33 patients with carcinoma of the gallbladder were investigated. A pair of mirror-image sections were obtained from each of the dissected lymph nodes and then stained using standard HE and immunohistochemical methods utilizing a monoclonal antibody against cytokeratin 7. The HE- and immunohistochemically stained sections were examined for the presence of tumor cells using light microscopy. RESULTS: All 78 lymph nodes from 12 patients with early gallbladder carcinoma were negative for both HE- and cytokeratin-positive cancer cells. Of 353 lymph nodes from 21 patients with advanced gallbladder carcinoma, HE staining showed that 98 were metastasis-positive. Among these 98 lymph nodes, 95 (97%) proved to be positive for metastasis based on cytokeratin immunostaining. On the other hand, the remaining 255 lymph nodes were cancer-free on the basis of HE staining results. Of the 255 HE-negative lymph nodes, seven (2.7%) were found to be positive for micrometastasis on the basis of cytokeratin staining. CONCLUSIONS: Cytokeratin staining of dissected lymph nodes is a useful new diagnostic tool for detecting micrometastatic foci in regional lymph nodes of patients with gallbladder carcinoma.     

Recurrence after radiotherapy for glottic carcinoma

A series of 478 patients with T1-3N0 glottic carcinoma treated by irradiation is presented. Of these patients, 320 were previously untreated, whereas 158 patients were referred for treatment of a recurrence after receiving radiotherapy elsewhere. The primary recurrence rate in the previously untreated patients was 10%. The rate was higher in T2 and T3 tumors, poorly differentiated tumors, and in patients who were in poor general condition. Over 80% of the recurrent tumors were Stage pT3 or pT4, whereas 12% of total laryngectomy specimens showed necrosis only with no evidence of tumor. The necrosis rate in previously untreated patients was 1% for T1 tumors, 4% for T2 tumors, and 3% for T3 tumors. Of all tumors, 60% were transglottic when they recurred, whereas only 29% were confined to the glottis at recurrence. Histologic diagnosis had a high sensitivity but a low specificity, indicating that a negative histologic report is unreliable. Of patients with a recurrent primary tumor, 13% were untreatable. The 5-year survival after a primary recurrence was 39%, and the main prognostic factors were sex, T stage at recurrence, and time to recurrence. Of patients available for follow-up at 5 years 49% were alive with a larynx, 5% were alive without a larynx, 13% were dead of the original cancer, and 33% had died of other causes. In those suffering a primary recurrence, the commonest cause of death was a subsequent lymph node metastasis, followed in order of frequency by stomal recurrence and recurrence in the pharyngeal remnant. The hospital mortality rate after laryngectomy was 3%, and 30% of patients undergoing laryngectomy developed a pharyngocutaneous fistula. The recurrence rate in lymph nodes was 14% at 5 years, general condition and T stage being the only significant predictors of recurrence. Only 17% of patients had small (N1) nodes by the time the diagnosis of cervical lymph node recurrence was made, and 27% of all patients were unsuitable for treatment. Host, tumor factors, and time to recurrence were not significant predictors of survival after node recurrence. The survival rate 5 years after node recurrence was 16%, and the main cause of death in those who died was uncontrolled disease in the neck. The hospital mortality after salvage neck dissection was 4.7%.     

T3 disease at presentation or pathologic involvement of four or more lymph nodes predict for locoregional recurrence in stage II breast cancer treated with neoadjuvant chemotherapy and mastectomy without radiotherapy

PURPOSE: To help define the clinical and pathologic predictors of locoregional recurrence (LRR) in breast cancer patients treated with neoadjuvant chemotherapy and mastectomy without radiotherapy for early-stage disease. METHODS AND MATERIALS: We retrospectively reviewed the outcomes of all 132 patients with Stage I or II breast cancer treated in prospective institutional trials with neoadjuvant chemotherapy and mastectomy without radiotherapy between 1974 and 2001. The clinical stage (American Joint Committee on Cancer 1988) at diagnosis was I in 5%, IIA in 46%, and IIB in 49% of patients. The median age at diagnosis was 49 years. All patients were treated with either a doxorubicin-based neoadjuvant regimen or single-agent paclitaxel. The total LRR rates were calculated by the Kaplan-Meier method, and comparisons were made with two-sided log-rank tests. The median follow-up was 46 months. RESULTS: The actuarial LRR rate at both 5 and 10 years was 10%. Factors that correlated positively with LRR included clinical Stage T3N0 (p = 0.0057), four or more positive lymph nodes at surgery (p = 0.0001), age < or =40 years at diagnosis (p = 0.0001), and no use of tamoxifen. In the patients who did not receive tamoxifen, estrogen receptor-positive disease correlated positively with LRR (p = 0.0067). The 5-year LRR rate for the 42 patients with clinical Stage T1 or T2 disease and one to three positive lymph nodes at surgery was 5% (only two events). CONCLUSIONS: For patients with clinical Stage II breast cancer, T3 primary disease, four or more positive lymph nodes after chemotherapy, and age < or =40 years old predicted for LRR. For most patients with clinical T1 or T2 disease and one to three positive lymph nodes, the 5-year risk for LRR was low, and the routine inclusion of postmastectomy radiotherapy does not appear to be justified.     

Detection of mutated K12-ras in histologically negative lymph nodes as an indicator of poor prognosis in stage II colorectal cancer

Stage II colorectal carcinoma is characterized by negative lymph node pathology as determined by conventional microscopic examination. These patients generally do not receive adjuvant therapy although 20%-30% will die from metastatic disease. To determine whether K-ras mutations at codon 12 could be used as a sensitive indicator of occult lymph node metastasis in stage II colon carcinoma, a retrospective study was performed using restriction endonuclease-mediated selective polymerase chain reaction (REMS-PCR) amplification. Of 106 colonic tumors analyzed, 46 were identified as positive for a K12-ras mutation in the primary tumor. Multiple lymph node samples from 38 of these 46 patients were examined by a sensitive nested PCR protocol for the presence of a K12-ras mutation. Of these 38 patients, 14 had 1 or more positive lymph nodes by PCR (37%) and 24 were negative for the mutation (63%). Of the 14 patients with a K12-ras mutation detected in lymph nodes, 8 died of the disease within 5 years (57%) compared to only 4 of the 24 patients with ras-negative lymph nodes (17%). The difference in time to death from disease, stratified using K12-ras status of lymph nodes, was statistically significant (P = 0.036; log-rank test). These results suggest K-ras mutation status of lymph nodes in patients with stage II colon cancer might identify a subgroup of patients who are more likely to develop recurrent and/or metastatic disease and benefit from adjuvant therapy. Larger studies are indicated to determine whether detection of K-ras mutation positivity in histologically negative lymph nodes portends a poor prognosis and to determine whether more aggressive use of adjuvant therapy is warranted.