Examination Of Regional Nodes Research Articles

Optimal surgical procedure for treating early-stage adenoid cystic carcinoma of the breast

To explore the superiority of breast conservation surgery (BCS) to mastectomy in treating early-stage adenoid cystic carcinoma of the breast (BACC). Patients with surgically treated stage I/II BACC were enrolled between 2000 and 2019 in the SEER database; they were divided into the BCS and mastectomy groups. Overall survival (OS) and disease-specific survival (DSS) were compared between the two groups, and Cox hazard regression models were used to determine the independent predictors. Of the 583 patients in the study, 386 were included in the BCS group. The 10-year OS rates for the BCS and mastectomy groups were 78% (95% CI: 74–82%) and 76% (95% CI: 70–82%), respectively, but the difference was not statistically significant (p = 0.968). The 10-year DSS rates for the BCS and mastectomy groups were 95% (95% CI: 93–97%) and 89% (95% CI: 85–93%), respectively, and the difference was statistically significant (p = 0.002). Pathological examination of regional lymph nodes and adjuvant treatment were not associated with improved OS or DSS, but age, disease grade, and lymph node metastasis were independent prognostic factors. For stage I/II BACC, BCS can achieve more satisfactory 10-year OS and DSS than mastectomy.

Identification of Spatial Proteomic Signatures of Colon Tumor Metastasis: A Digital Spatial Profiling Approach

Over 150,000 Americans are diagnosed with colorectal cancer (CRC) every year, and annually >50,000 individuals will die of CRC, necessitating improvements in screening, prognostication, disease management, and therapeutic options. CRC tumors are removed en bloc with surrounding vasculature and lymphatics. Examination of regional lymph nodes at the time of surgical resection is essential for prognostication. Developing alternative approaches to indirectly assess recurrence risk would have utility in cases where lymph node yield is incomplete or inadequate. Spatially dependent, immune cell-specific (eg, tumor-infiltrating lymphocytes), proteomic, and transcriptomic expression patterns inside and around the tumor-the tumor immune microenvironment-can predict nodal/distant metastasis and probe the coordinated immune response from the primary tumor site. The comprehensive characterization of tumor-infiltrating lymphocytes and other immune infiltrates is possible using highly multiplexed spatial omics technologies, such as the GeoMX Digital Spatial Profiler. In this study, machine learning and differential co-expression analyses helped identify biomarkers from Digital Spatial Profiler-assayed protein expression patterns inside, at the invasive margin, and away from the tumor, associated with extracellular matrix remodeling (eg, GZMB and fibronectin), immune suppression (eg, FOXP3), exhaustion and cytotoxicity (eg, CD8), PD-L1-expressing dendritic cells, and neutrophil proliferation, among other concomitant alterations. Further investigation of these biomarkers may reveal independent risk factors of CRC metastasis that can be formulated into low-cost, widely available assays.

Social determinants and facility type impact adherence to best practices in operable IIIAN2 lung cancer.

We aimed to identify patient- and facility-specific predictors of collective adherence to 4 recommended best treatment practices in operable IIIAN2 non-small-cell lung cancer (NSCLC) and test the hypothesis that collective adherence is associated with superior survival. We queried the National Cancer Database for clinical stage IIIAN2 NSCLC patients undergoing surgery during 2010-2015. The following best practices were examined: performance of an anatomic resection, performance of an R0 resection, examination of regional lymph nodes and administration of induction therapy. Multivariable regression models were fitted to identify independent predictors of guideline-concordance. We identified 7371 patients undergoing surgical resection for IIIAN2 lung cancer, of whom 90.8% underwent an anatomic resection, 88.2% received an R0 resection, 92.5% underwent a regional lymph node examination, 41.6% received induction therapy and 33.7% received all 4 best practices. Higher income, private insurance and treatment at an academic facility were independently associated with adherence to all 4 best practices (P < 0.01). A lower level of education and residence in a rural county were associated with a lack of adherence (P < 0.05). Adherence to all 4 practices correlated with improved survival (P < 0.01). National adherence to best treatment practices in operable IIIAN2 lung cancer was variable as evidenced by the majority of patients not receiving recommended induction therapy. Socioeconomic factors and facility type are important determinants of guideline-concordance. Future efforts to improve outcomes should take this into account since guideline concordance, in the form of collective adherence to all 4 best practices, was associated with improved survival.

The state of regional lymph nodes in chronic tonsillitis according to ultrasound

Is development of a method for differential diagnosis of complicated (toxic-allergic) and uncomplicated (simple) forms of chronic tonsillitis. 147 patients were divided into 2 groups: 1) 61 (42%) - with a simple form and 2) 86 (58%) - with a toxic-allergic form of chronic tonsillitis of the II degree. Patients underwent ultrasound examination of regional lymph nodes, to determine their localization, quantity (single, multiple), shape, size and structure. According to ultrasound data, it was revealed that for the simple form of chronic tonsillitis the following characteristics of the lymph nodes were typical - bean-like form, single, clear contours, homogeneous central parts and reduced vascularization; for the toxic-allergic form of chronic tonsillitis, the following characteristics of lymph nodes were revealed - oval shape, lymph nodes conglomerates, hypoechoic central parts, increased vascularization and irregular shape of the gates. The proposed method allows to quickly and efficiently conduct differential diagnosis of chronic tonsillitis. This technique is easily reproducible in the conditions of any (outpatient, inpatient) medical facility using standard equipment for ultrasound examination, does not require the use of any drugs.

Isolated tumor cells in regional lymph nodes in patients with adenocarcinoma of the esophagogastric junction might represent part of true metastases

Regional lymph node metastases in patients with carcinoma of the esophagogastric junction (EGJ) are an important prognostic factor. According to the tumor, node, and metastasis classification, isolated tumor cells (ITCs) are single tumor cells or small clusters of tumor cells not exceeding 0.2 mm. Tumor clusters >0.2 mm are classified as metastases. The significance of lymph nodes with ITCs is unclear, although not contributing to the pN category. The aim of this study was to determine the prevalence of regional lymph nodes with ITCs on the primary hematoxylin and eosin-stained slide and to examine how often deeper sections reveal a true metastasis. The study included surgical specimens of 126 patients with adenocarcinoma of the EGJ. Lymph nodes with ITCs were identified. Additional sections were cut and stained with hematoxylin and eosin and with cytokeratin. All slides were evaluated for the presence of tumor cells, and it was determined whether the criteria for a metastasis were met on the additional sections. ITCs were detected in 59 (1.7%) of 3454 lymph nodes and in 41 (32.5%) of 126 patients. In 29 (49.2%) lymph nodes with ITCs on the primary slide, further sections resulted in a changed status from ITCs to a metastasis. In 7 (17.1%) of 41 patients, the pN category was changed. In patients with adenocarcinoma of the EGJ, the presence of ITCs in regional lymph nodes is a common observation. ITCs often represent part of a real metastasis. To obtain a pN category as accurate as possible, we strongly recommend thorough examination of regional lymph nodes with additional sections when ITCs are observed.

Clinicopathologic implication of meticulous pathologic examination of regional lymph nodes in gastric cancer patients

BackgroundWe aimed to investigate effect of increased number of examined lymph nodes (LNs) to pN category, and compare various N categories in gastric cancer: American Joint Committee on Cancer (AJCC) 7th edition, metastatic LN ratio (MLR), and log odds of positive LNs (LODDS).MethodsFour cohorts with a total of 2,309 gastric cancer patients were enrolled. For cohort 1 and 2, prognostic significance of each method by disease-specific survival was analyzed using Akaike and Bayesian information criterion (AIC and BIC).ResultsThe total LNs in four cohorts significantly differed [median (range), 28 (6–97) in cohort 1, 37 (8–120) in cohort 2, 48 (7–122) in cohort 3, and 54 (4–221) in cohort 4; p<0.001]. The numbers of negative LNs increased with increase of total LN (p<0.001), but the numbers of metastatic LNs did not increase from cohort 1 to 4. MLR and LODDS in four cohorts had decreasing tendency with increase of total LNs in each pT3 and pT4 category (p<0.001), while the numbers of metastatic LNs did not differ significantly in any pT category (p>0.05). The AIC and BIC varied according to different cut-off values for MLR; model by cut-offs of 0.2 and 0.5 being better for cohort 1, while cut-offs 0.1 and 0.25 was better for cohort 2.ConclusionOur study showed that the number of metastatic LNs did not increase with maximal pathologic examination of regional LNs. AJCC 7th system is suggested as the simplest method with single cut-off value, but prognostic significance of MLR may be influenced by various cut-offs.

Fatal Case of Metastatic Cellular Fibrous Histiocytoma

Cellular fibrous histiocytoma was first described in 1994 as a distinct variant of fibrous histiocytoma. Since then, at least 21 cases of cellular fibrous histiocytomas metastasizing to regional lymph nodes and/or lungs have been described, though not all fatal. We report the case of a 68-year-old male patient who presented with a large ulcerated skin tumor on the left thigh. The lesion was urgently excised. Histopathological examination led to the diagnosis of cellular fibrous histiocytoma. Nine months later, the patient presented with progressive dyspnea. A thoracoabdominal computed tomography revealed diffusely spread nodular lung lesions. A lung biopsy confirmed them to be metastases of the cellular fibrous histiocytoma. The condition of the patient quickly deteriorated, and he deceased 2 months later. Given the possible aggressive nature of cellular type of fibrous histiocytoma, we advice complete excision and clinical follow-up. Chest x-rays and ultrasound examination of regional lymph nodes should be performed in atypical lesions.

Previstage GCC colorectal cancer staging test: a new molecular test to identify lymph node metastases and provide more accurate information about the stage of patients with colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of death for both men and women in North America. The staging of the CRC at the time of diagnosis is the single most important prognostic factor in determining recurrence and survival. Until 2008, accurate evaluation of CRC stages I and II was based on examination of regional lymph nodes (LNs) under a microscope to identify cancer cells. This method can detect one cancer cell in 200 normal cells, but analyzes only a fraction of the available tissue from the LN (less than 0.1%). Up to 30% of patients assessed by traditional histopathology methods as having stage II disease (negative LNs) experience a recurrence of their cancer. Previstage GCC Colorectal Cancer Staging Test, a new molecular diagnostic test, is able to identify patients at high risk of recurrence by examining their LNs for guanylyl cyclase C (GCC). GCC is a marker found in cells lining the lumen of the gastrointestinal tract. The expression of GCC is conserved in CRC and metastatic disease. Using an ultrasensitive quantitative reverse transcription (RT)-PCR, the test interrogates a patient's LN tissues to identify GCC levels consistent with metastatic (stage III) disease. The technology employed in Previstage GCC is nearly 100,000 times more sensitive than microscopic staging methods. This molecular diagnostic test allows a more thorough examination of LNs and has an analytic sensitivity of 92% and a specificity of 98%. Such a test can be used to overcome the limitations of staging by traditional histopathology alone.

Ultrasound assessment of lymph nodes in the management of early‐stage melanoma

It has been suggested that ultrasound examination of regional lymph nodes provides staging and prognostic information that is as accurate as sentinel node biopsy in patients who present with cutaneous melanoma. However, in most studies the sensitivity of ultrasound in detecting nodal metastasis has been low (23% in a recent large series). For the present, sentinel node biopsy remains the most accurate method of regional node staging in patients with newly diagnosed melanoma.

Gastrointestinale Tumoren

Removal and examination of regional lymph nodes play an important role in the surgical therapy of gastrointestinal tumors concerning potential adjuvant treatment strategies. The number of metastatic regional lymph nodes as well as the number of removed and examined lymph nodes are of importance regarding estimation of the prognosis. It is essential to consider which lymph nodes are defined as regional in the UICC TNM classification and which definitions apply for the individual N categories. Furthermore, it is necessary to define which recommendations are valid for the minimum numbers of lymph nodes to be removed and examined for particular tumor entities.

Please, Sir, pull down your socks!

After leaving the examination bed, he sat down once again and the doctor commented on the result of the last early cytomegalovirus antigen (p65) test, again positive irrespective of the course of ganciclovir administered the previous month. A further course of antiviral drug was scheduled, then the patient was dismissed. At this point, while the patient was crossing to the door, the young fellow stopped the patient: “Please, Sir” – he said – “pull down your socks!”. Two little violet nodules appeared on the upper surface of the left foot (Fig. 1). “Here you are!” – said the fellow as a good new. After the disclosure of the two nodules, the examination of regional lymph nodes (another very frequently skipped phase of physical examination) becomes mandatory. In our patient no nodes were found at the groin. Some days after, a punch biopsy confirmed a Kaposi’s sarcoma (KS) at the plaque stage. Immunosuppression was lightened and the sarcoma regressed and finally disappeared. Finally, his graft function is still stable after reduction of immunosuppressive therapy. Soon after the surgery his immunosuppressive treatment (cyclosporine, azatioprine and steroids) had to be tapered because of toxicity of calcineurine inhibitor and sub-clinical cytomegalovirus infection. Nevertheless, two months after the graft, he suffered from a urinary tract infection by K. pneumoniae, treated with amoxicillin clavulanate. Renal function was only sub-optimal due to an unfavourable match between donor kidney and patient body size; serum creatinine nadir was 2 mg/dl (38.1 ml/min calculated glomerular filtration rate). The occurrence of different infections suggested overimmunosuppression. His sexual profile was not investigated further. As written in medical texts, lesions of KS are characteristic and are not difficult to diagnose [1], but it is necessary to be aware of their occurrence in a specific clinical setting.

Is the clinical staging system a good choice in the staging of vulvar malignancies?

Dear Sir, We have read the article by Sergi Vidal-Sicart and coworkers [1] entitled “Validation and application of the sentinel lymph node concept in malignant vulvar tumours”, published in the March 2007 issue of the European Journal of Nuclear Medicine and Molecular Imaging. We agree with the authors that sentinel lymph node (SLN) identification permits the accurate pathological examination of regional nodes and could reduce the high morbidity of current surgical treatment in vulvar tumour patients. The results are impressive; however, there are some controversies in the explanation for the tumour stage in SLN-positive cases. The clinical stage of vulvar cancers is at least III when lymph node positivity is found. In the publication of Sergi Vidal-Sicart, however, there are ten patients listed with positive SLN, classified as stage Ib or II. During the past 5 years our team has been involved in the development and application of the method of SLN sampling in vulvar neoplasms to determine the level of progression of the disease. Our preliminary results suggest that sentinel node scintigraphy is a reliable method in early vulvar carcinoma and melanoma [2]. An occasional survey was written by us on the comparison of the TNM and clinical (FIGO) staging systems in different gynaecological malignancies. In 1969 FIGO introduced a staging system for vulvar cancer based on the TNM classification, utilising the clinical assessment of tumour size, tumour site, status of the regional lymph nodes and a limited search for distant metastases. The most serious drawback of this staging system was the inaccuracy of clinical assessment in determining groin node status, especially given that microscopic metastases may be present in clinically normal nodes and cancer-free nodes may be enlarged by inflammation [3]. The TNM system is a dual system distinguishing between a clinical (pretreatment) classification (TNM or cTNM) and a pathological (post-surgical histopathological) classification (pTNM). Thus, in TNM, each patient is staged clinically as well as pathologically. We should realise that not only surgical and pathological, but also clinical staging is important. We should continue to rely upon clinical staging when planning treatment and making prognostic assessments [4]. In the case of vulvar carcinoma, the TNM staging system is obviously superior to clinical (FIGO) staging. Of all the gynaecological malignancies, vulvar carcinoma is the one for which the SLN concept is most relevant. We suggest that in publications dealing with SLN investigations, TNM staging should be preferred over clinical staging. Eur J Nucl Med Mol Imaging (2007) 34:1878–1879 DOI 10.1007/s00259-007-0511-5

Differenzialdiagnose und Therapieoptionen bei Tumoren der Konjunktiva

The diagnostic classification of most conjunctival tumors is based on case history, inspection, and examination with the slit lamp microscope. Further imaging procedures are rarely indicated when malignant processes are not circumscribed. Clinical classification then also includes palpation and echographic examination of regional lymph nodes. Pigmented and nonpigmented melanocytic nevi are the most frequent conjunctival tumors. An important practical biomicroscopic cardinal symptom of the most frequent nevi is the presence of epithelial pseudocysts. Essential in practice is the histopathological confirmation of the clinical diagnosis, e.g., distinguishing between nonpigmented melanomas and sebaceous gland carcinomas with a pagetoid growth pattern or squamous cell carcinomas. Depending on the course and findings, the following therapeutic measures can be indicated: cryotherapy, chemotherapy, radiotherapy, modified enucleation, orbital exenteration, or a combination of different methods.

Multiple lymph node metastases in a boy with primary testicular carcinoid, despite negative preoperative imaging procedures

A testicular tumor in a 12-year-old boy proved to be a carcinoid tumor. An extensive investigation including a computed tomographic scan of the abdominal and pelvic region as well as both 123I-labeled metaiodobenzylguanidine and 111In-coupled octreotide scintigraphy was normal. Because histopathologic examination of the primary surgical specimen revealed tumor growth in the resection border of the spermatic vessels, a second operation with unilateral lymph node dissection was performed. Surprisingly, 3 lymph node metastases were found. No further treatment was given and the boy is alive without disease 9 years after surgery. This case illustrates that modern scintigraphic techniques do not always detect carcinoid tumors. Because carcinoids respond poorly to other treatment modalities, the importance of initial radical surgery including a meticulous examination of regional lymph nodes is emphasized.

Reducing the Need for Sentinel Node Procedures by Ultrasound Examination of Regional Lymph Nodes

In this issue of Annals of Surgical Oncology, Starritt et al. present their experience with ultrasound (US) examination of sentinel nodes (SNs) in the initial assessment of patients with primary cutaneous melanoma. In 304 patients, histopathology of the SN revealed metastatic disease in 33 node fields in 31 patients. Only 7 of 33 node fields had been also identified by US. Metastatic deposits <4.5 mm had not been identified by US. The authors concluded that because most metastatic deposits in SNs are smaller, US is not cost-effective in this setting. The authors suggest, on the basis not of their own findings, but of the results of a study by Garbe et al. (which demonstrated that the ability of US to detect melanoma recurrence in lymph nodes during followup was greatest in stage IIb patients), that in this subset of patients with more aggressive melanomas, US of the SN in the primary assessment is likely to be positive more often and should therefore be considered. This is mixed message indicating that this chapter is not closed. In breast cancer, it has been clearly demonstrated that US of the axilla can reduce the number of SN procedures. A multicenter study in 116 patients in Rotterdam demonstrated in 1999 that US-guided fine-needle aspiration (US-FNA) identified positive lymph nodes in 17% of clinically node-negative cancer patients. For T1 tumors, the detection rate for US-FNA was only 6%, but for T2 tumors it was 25%, and for T3 tumors it was 50%. This was recently confirmed in a Japanese study in 262 women, in which US was positive in 6% of T1, 20% of T2, and 70% of T3 tumors. These findings indicate that USFNA can significantly reduce the number of SN procedures and that it is cost-effective in breast cancer for T2/3 tumors. Similar results were also reported by Deurloo et al. in 266 patients. These authors demonstrated a reduction of SN procedures of 14% in the overall clinically node-negative breast cancer population. In melanoma, one might expect a similar situation, and indeed there are reports pointing in that direction. Rossi et al. published a prospective study on the preoperative assessment of the regional lymph nodes by US in 125 patients with primary cutaneous melanoma. US correctly detected 12 of 31 histologically positive lymphatic basins in the total population of 125 patients and thus avoided an SN procedure in approximately 10% of patients. Whether this 10% reduction for the total population of melanoma patients considered for SN is cost-effective remains to be shown, because no formal calculations were presented. Of note, in this article, no metastasis <2 mm was picked up by US. Starritt et al. correctly note that there is no formal proof in the report by Rossi et al. that a different node with a different-sized micrometastasis from the histopathologically reported SN was not detected by US. Still, the 10% reduction of SN procedures, as the outcome of the Rossi study stands, is not that much different from the 14% to 17% reported in overall breast cancer populations, and that result is the most important outcome. Moreover, the conclusion that the yield will be higher if one implements US only in thicker melanomas, be Received September 13, 2004; accepted October 18, 2004. Address correspondence and reprint requests to: Alexander M. M. Eggermont, MD, PhD; E-mail: a.m.m.eggermont@ erasmusmc.nl.

Detection of Micrometastases of Breast Cancer by Immunohistochemical Analysis of Cytokeratin.

Axillary lymph node metastases are the single most important predictor of overall survival in patients with breast cancer. Micrometastases are defined by the American Joint Committee on Cancer as tumor foci less than or equal to 2 mm in greatest dimension. Recently, up to 30% of breast cancer patients were reported to have micrometastases. In this paper, to assess the rate of micrometastases in patients with stage I breast cancer, we attempted to determine the most useful marker of the micrometastases in node negative cases by routine histopathologic examination of regional lymph nodes and comparison of the results with the influencing factors on prognosis. We performed immunohisto chemical staining for pancytokeratin, cytokeratin 7, cytokeratin 20 and CEA to identify which protein was the most useful marker for the detection of micrometastases in 86 node negative cases and determined the correlation between histological and clinical data. A total of 5 lymph nodes in 5 separate cases showed micrometastases among the total 1,296 lymph nodes and 86 cases. The rates of micrometastases of lymph nodes and cases were 0.38% and 5.8%, respectively. The tumor type of micrometastasis was infiltrating ductal carcinoma in all cases. None of the microme tastases cases showed any relationship with tumor grade, tumor size, expression of ER and PR, patient survival rate or recurrence rate. The most useful marker to detect micrometastases was pancytokeratin. The results of this study indicate that micrometastasis of axillary lymph nodes does not carry any independent prognostic significance.

Ultrasound examination of regional lymph nodes significantly improves early detection of locoregional metastases during the follow-up of patients with cutaneous melanoma: results of a prospective study of 1288 patients.

In regional lymph node metastasis of cutaneous melanoma, the number and volume of involved lymph nodes are the most important prognostic factors. Several studies have revealed that palpation of the lymphatic drainage area(s) and regional lymph nodes has a high rate of false-negative results during follow-up. The aim of the current study was to assess the sensitivity and specificity of ultrasound versus clinical diagnosis in the detection of subcutaneous and regional metastases. During a period of 42 months, a total of 6328 lymphatic drainage areas were examined clinically and by ultrasound (7.5-10 MHz) in 1288 melanoma patients at 4435 follow-up consultations. When an ultrasound finding was suggestive of metastasis, surgery and histopathologic evaluation were performed. The results of clinical examination, ultrasound examination, and histopathologic findings were compared. In 504 ultrasound examinations performed on 235 patients, metastatic disease was diagnosed in 263 examinations following surgery (179 patients). Due to advanced disease or rejection, an additional 56 patients did not undergo surgery. In 239 of the 263 positive findings (90.9%), metastases from melanoma were histopathologically confirmed. In 8 cases (3%) a second malignancy and in 16 cases (6. 1%) benign lymphadenopathy was histopathologically diagnosed. Palpation of subcutaneous lymph nodes and lymph nodes gave false-negative results in 68 of the 238 cases of histopathologically proven metastases (28.6%). Clinical examination was least sensitive in the supraclavicular, axillary, and infraclavicular regions. The sensitivity and specificity for ultrasound examination were 89.2% and 99.7%, respectively, and 71.4% and 99.7% for clinical examination, respectively. For early diagnosis of in-transit and regional lymph node metastases in cutaneous melanoma, ultrasound scanning is distinctly superior to clinical examination. Controlled follow-up studies are proposed to examine the possible beneficial effects on survival time resulting from the ultrasound examinations of the lymphatic drainage area(s) and regional lymph nodes.

Examination of Regional Lymph Nodes by Sentinel Node Biopsy and Molecular Analysis Provides New Staging Facilities in Primary Cutaneous Melanoma

Histopathologic parameters of the primary tumor, such as Breslow's tumor thickness and Clark's level of invasion are the current basis for prognostic classifications of primary cutaneous melanoma. Once patients develop regional node metastasis, histopathologic features of the primary melanoma no longer contribute significantly to survival prediction. In this tumor stage, the extent of lymph node involvement is the main prognostic factor. This study addresses the question whether application of a highly sensitive molecular biology assay for detection of submicroscopic melanoma cells in sentinel lymph nodes may be suitable to improve melanoma staging. One hundred and sixteen patients with primary cutaneous melanoma with a total of 214 sentinel lymph nodes were enrolled. Sentinel lymph nodes were analyzed by histopathology including immunohistochemistry and by reverse transcription-polymerase chain reaction for tyrosinase. Patients were examined for tumor recurrences during a follow-up period of 19 mo (median). Disease-free survival probabilities were calculated and independent prognostic factors were determined by multivariate analysis. Using histopathology, micrometastatic nodal involvement was detected in 15 patients (13%). Of the 101 patients with histopathologically negative sentinel lymph nodes, 36 were reclassified by positive tyrosinase reverse transcription-polymerase chain reaction and 65 patients were still negative by reverse transcription-polymerase chain reaction. Recurrences were observed in 23 (20%) of 116 patients. These tumor recurrences were demonstrated in 10 patients (67%) with histopathologically positive sentinel lymph nodes, in nine patients (25%) with submicroscopic tumor cells detected by reverse transcription-polymerase chain reaction, and in four patients (6%) negative by both methods. The differences in recurrence rates were statistically significant (p = 0.01). In a multivariate analysis, histopathologic and reverse transcription-polymerase chain reaction status of the sentinel lymph node were demonstrated to be the only significant prognostic factors for predicting disease-free survival. Tyrosinase reverse transcription-polymerase chain reaction for the detection of minimal residual melanoma in sentinel lymph nodes is a powerful tool to determine patients who are at increased risk for subsequent metastasis. Moreover, a group of patients with high tumor thickness was identified by negative reverse transcription-polymerase chain reaction to be at low risk for recurrent disease. These data may have an impact on future tumor classifications of primary cutaneous melanoma.

Axillary Node Micrometastases: Detection and Biologic Significance.

Axillary lymph node status is the single most important predictor of overall survival in patients with breast cancer. Standard histopathologic examination of regional lymph nodes relies on one microscopic section of each node to detect metastatic disease. The spectrum of metastatic disease in a lymph node ranges from complete replacement of the node by tumor to isolated nests of tumor cells in the subcapsular sinus. The clinical significance of micrometastases in axillary lymph nodes has changed over time. Micrometastases are defined by the American Joint Committee on Cancer as tumor foci less than or equal to 2 mm in greatest dimension. Retrospective studies of node-negative breast cancer patients employing intensive histopathologic examination of the axillary lymph nodes consistently show that up to a third of these patients are actually node positive. Studies published through the mid-1980s failed to show any significant effect of these micrometastases on survival. More recent studies (mid-1980s-1997) with more than 10 years of clinical follow-up have come to a different conclusion. It now appears that micrometastases are associated with a small, but statistically significant, decrease in tumor-free survival and overall survival, as compared with truly node-negative breast cancer patients. Additional slides stained with hematoxylin and eosin ("levels"), immunohistochemistry for cytokeratin proteins (found only in epithelial cells), and reverse transcriptase polymerase chain reaction for cytokeratin protein mRNA have all been used to detect micrometastases in recently published studies. The methodology utilized to detect micrometastases clearly affects the sensitivity of their detection. The current issue is the most appropriate method of detection of these small foci of tumor, given technical and cost considerations. The clinical significance of single malignant cells in the subcapsular sinus of lymph nodes, identified only by immunohistochemistry or molecular techniques, remains unclear.

Adenocarcinoma of the pancreas

Stage I (T1-2NOM0) adenocarcinoma of the pancreas is associated with a 5-year survival rate of 15-25%. Despite apparently curative resection and pathologic staging indicating localized disease, these cancers recur. The authors hypothesized that there exists microscopic regional disease that is not detected by surgical exploration or routine histopathology. Because 90-95% of pancreatic cancers exhibit codon 12 K-ras mutations, the authors examined regional lymph nodes for mutated K-ras as a marker of metastasis. DNA was extracted from paraffin embedded archival specimens (primary tumors and histologically negative lymph nodes) of patients with Stage I pancreatic adenocarcinoma. The target region of K-ras was amplified by polymerase chain reaction (PCR) and tested for codon 12 mutation by BstN1 restriction digestion (restriction fragment length polymorphism [RFLP]) that recognized normal but not mutated sequences. Cell lines that harbored normal or mutated K-ras and resected jejunum or gallbladder were used as controls. The regional lymph nodes of 22 patients whose tumors harbored mutated K-ras were tested. Dilution experiments with normal and mutant control cell line DNA demonstrated an assay sensitivity for mutated K-ras of 0.1%. Mutated K-ras was found in at least 1 regional lymph node in 16 (73%) of 22 patients with pathologic Stage I pancreatic adenocarcinoma, which suggested metastases not detected by routine histopathology. DNA sequence analysis was performed in four patients and confirmed identical point mutations in the primary tumor and accompanying PCR/RFLP positive lymph nodes. Pathologic examination of regional lymph nodes in pancreatic adenocarcinoma specimens fails to detect metastases in many patients. Lymph node micrometastasis is one reason for the poor survival rates observed among patients with Stage I cancers. PCR/RFLP may have a role in staging early pancreatic cancers.