Patients at risk for peritoneal surface malignancy of colorectal cancer origin: the role of second look laparotomy.

Peritoneal surface malignancy (PSM) is a frequent occurrence in the natural history of colorectal cancer (CRC). Although significant advances have been made in screening of CRC, similar progress has yet to be made in the early detection of PSM of colorectal cancer origin. The fact that advanced CRC can be confined to the peritoneal surface without distant dissemination forms the basis for aggressive multi-modality therapy consisting of cytoreductive surgery (CRS) plus hyperthermic intra-peritoneal chemotherapy (HIPEC), and neoadjuvant and/or adjuvant systemic therapy. Reported overall survival with complete CRS+HIPEC exceeds that of systemic therapy alone for the treatment of PSM from CRC, underscoring the advantage of this multi-modality therapeutic approach. Patients with limited peritoneal disease from CRC can undergo complete cytoreduction, which is associated with the best reported outcomes. As early or limited peritoneal carcinomatosis is undetectable by conventional imaging modalities, second look laparotomy is an important means to identify disease in high-risk patients at a stage most amenable to complete cytoreduction. This review focuses on the identification of patients at risk for PSM from CRC and discusses the role of second look laparotomy.

Thermal ablation of hepatic malignancy: useful but still not optimal.

The mortality associated with primary and metastatic hepatic malignancies remains high because few patients are candidates for hepatic resection or transplantation. Resection is the most effective treatment for liver tumors but may be contraindicated by factors such as the tumor's location; hepatic transplantation can cure primary hepatocellular carcinoma and underlying cirrhosis, but a donor may not be immediately available. When resection or transplantation is not possible, thermal ablation is a reasonable therapeutic option. Effective destruction of tumors can be achieved with low recurrence rates and minimal complications or risk of death. In patients with primary hepatic malignancy, ablation treatment does not preclude subsequent transplantation. Although radiofrequency ablation is currently the most widely used thermal ablative technique for hepatic malignancy, microwave ablation is gaining popularity and eventually may prove to be more effective.

Unfavourable prognosis associated with K-ras gene mutation in pancreatic cancer surgical margins.

BACKGROUND: Despite intent to cure surgery with negative resection margins, locoregional recurrence is common in pancreatic cancer. AIMS: To determine whether detection of K-ras gene mutation in the histologically negative surgical margins of pancreatic cancer reflects unrecognised disease. PATIENTS: Seventy patients who underwent curative resection for pancreatic ductal adenocarcinoma were evaluated. METHODS: All patients had surgical resection margins (pancreatic transection and retroperitoneal) that were histologically free of invasive cancer. DNA was extracted from these paraffin embedded surgical margins and assessed by quantitative real time polymerase chain reaction to detect the K-ras gene mutation at codon 12. Detection of K-ras mutation was correlated with standard clinicopathological factors. RESULTS: K-ras mutation was detected in histologically negative surgical margins of 37 of 70 (53%) patients. A significant difference in overall survival was demonstrated between patients with margins that were K-ras mutation positive compared with negative (median 15 v 55 months, respectively; p = 0.0008). By univariate and multivariate analyses, detection of K-ras mutation in the margins was a significant prognostic factor for poor survival (hazard ratio (HR) 2.8 (95% confidence interval (CI) 1.5-5.3), p = 0.0009; and HR 2.8 (95% CI 1.4-5.5), p = 0.004, respectively). CONCLUSIONS: Detection of cells harbouring K-ras mutation in histologically negative surgical margins of pancreatic cancer may represent unrecognised disease and correlates with poor disease outcome. The study demonstrates that molecular-genetic evaluation of surgical resection margins can improve pathological staging and prognostic evaluation of patients with pancreatic ductal adenocarcinoma.

Quality control issues in the management of colon cancer patients.

Quality assurance in colon cancer demands a multidisciplinary effort involving general practitioners, surgeons, radiologists, gastroenterologists, medical oncologists, and pathologists, among others. Maximal improvements in survival will result when colon cancer screening, diagnosis, staging, treatment and surveillance are optimized. We seek to identify those issues most relevant to the quality of care we provide our colon cancer patients.

Ultrastaging of early colon cancer using lymphatic mapping and molecular analysis.

Approximately one-third of node-negative colon cancers will recur, possibly due to understaging and inadequate pathological examination of lymph nodes (LNs). We evaluated the sensitivity, accuracy and feasibility of staging based on lymphatic mapping, focused examination, and molecular analysis of the sentinel node (SN) in patients with primary colorectal carcinoma. Between 1996 and 2000, 100 patients with colon carcinoma (CRC) underwent lymphatic mapping immediately after peritumoral injection of 1.0 cc of isosulphan blue dye. All LNs in the CRC specimen were examined by routine haematoxylin and eosin (H&E) staining. Sentinel nodes were examined by step serial sectioning, cytokeratin immunohistochemistry (CK-IHC) and/or reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in an attempt to identify occult micrometastatic disease. Lymphatic mapping was successful in 97% of the cases. There were 5 false-negative cases, predominately associated with T3/T4 tumours. Aberrant lymphatic drainage was identified in 8 patients (8%) altering the operative approach. 26 patients had H&E-positive LNs. In 74 patients who were node-negative by routine H&E, 18 (24%) had occult nodal micrometastases missed on routine H&E examination, but detected by focused analysis of the SN. RT-PCR analysis of the SN was performed in 40 patients, 26 of which were negative by H&E and CK-IHC. In 12/26 (46%) of these patients, there was additional evidence of micrometastatic disease. In this study, focused examination of the SN in conjunction with RT-PCR analysis identified micrometastatic disease in a significant number of node-negative patients. This may have important implications when selecting patients for adjuvant treatment protocols.

Hepatic cytoreduction followed by a novel long-acting somatostatin analog: a paradigm for intractable neuroendocrine tumors metastatic to the liver.

BACKGROUND: Optimal management of symptomatic neuroendocrine tumors that metastasize to the liver is controversial. We investigated aggressive hepatic cytoreduction and postoperative administration of octreotide long-acting release (LAR), a long-acting somatostatin analog. METHODS: Between December 1992 and August 2000, 31 patients underwent hepatic surgical cytoreduction (20 carcinoid, 10 islet cell, and 1 medullary). All patients had progressive symptoms refractory to conventional therapy. RESULTS: Hepatic cytoreduction (resection, cryosurgery, and/or radiofrequency ablation) eliminated symptoms in 27 patients (87%) and decreased secretion of hormones by an overall mean of 59%. When minor symptoms returned and/or hormonal levels increased during follow-up, adjuvant therapy was started. Ten patients received adjuvant octreotide LAR once a month, and 21 received other adjuvants. At a median postoperative follow-up of 26 months, 16 patients had progressive/recurrent disease, 13 had died of their disease, and 2 remained free of disease. Median symptom-free interval was 60 months (95% confidence interval, 48-72) with octreotide LAR and 16 months (95% confidence interval, 10-29) with other adjuvants (P = .0007). Two-year symptom-free survival rate was 100% with octreotide LAR and 33% with other adjuvants. CONCLUSIONS: Hepatic surgical cytoreduction can palliate progressive symptoms associated with liver metastases from intractable neuroendocrine tumors. Postoperative adjuvant therapy with octreotide LAR can prolong symptom-free survival.

Lymphatic mapping improves staging during laparoscopic colectomy for cancer.

BACKGROUND: Recently, lymphatic mapping (LM) of the sentinel lymph node (SN) has been coupled with ultrastaging methods to diagnose nodal micrometastases from colorectal cancer (CRC). We have developed a technique for LM at the time of laparoscopic colon resection (LCR). METHODS: Between August 1996 and February 2000, 11 patients with small early-stage CRC underwent laparoscopic LM and LCR. The primary tumor/polyp site was visualized through a colonoscope and either tattooed preoperatively with a carbon dye (India ink), or stained intraoperatively by peritumoral injection of isosulfan blue dye. Immediately after intraoperative injection of blue dye, efferent lymphatic channels were visualized through the laparoscope and followed to the SN. Each blue-stained SN was marked with a suture or clip. RESULTS: In all 11 cases, laparoscopic LM identified between one and three SN draining the primary tumor. LM added ~15-20 min to the operating time. The SN correctly reflected the nodal status of the entire specimen in all cases. In the one node-positive case, micrometastases were found only in an SN and only after cytokeratin immunohistochemistry (CK-IHC). In four cases, LM demonstrated unexpected primary lymphatic drainage that prompted an increase in the margins of resection. CONCLUSIONS: LM during laparoscopic colectomy for CRC may be useful to mark the primary tumor site and to demonstrate lymphatic drainage that can alter the margins of resection. Focused examination of SN identifies occult micrometastases that up-stage CRC.

Aberrant drainage and missed micrometastases: the value of lymphatic mapping and focused analysis of sentinel lymph nodes in gastrointestinal neoplasms.

Lymph node analysis is essential for staging gastrointestinal (GI) neoplasms. Our group has conducted several studies of intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) for the staging of GI neoplasms. LM is performed following injection of 0.5-1 ml of isosulfan blue dye, and blue-stained sentinel lymph nodes (SLNs) are analyzed by hematoxylin and eosin (H&E) staining, multiple sectioning, and cytokeratin immunohistochemistry. In feasibility trials, LM identified at least one SLN in 121 of 126 patients. Of the 58 cases with nodal metastasis, 50 (89%) had at least one positive SLN and 24 (42%) had nodal metastasis only in the SLN. In 25 cases, tumor deposits were identified by multiple sectioning (n = 8) or immunohistochemistry (n = 17) only. In 10 cases (8%), LM identified aberrant lymphatic drainage that altered the extent of the lymphadenectomy. Our cumulative experience indicates that focused analysis of the SLNs draining GI neoplasms can increase the detection of micrometastases and may improve selection of patients for adjuvant treatment.

Ultrastaging of colorectal cancer by sentinel lymph node mapping technique--a multicenter trial.

Sentinel lymph node (SLN) mapping accurately diagnoses the status of nodal basin with >95% accuracy in melanoma and breast cancer. A multicenter trial for SLN mapping was performed on 203 patients with colorectal cancer to determine accuracy, upstaging, skip metastasis, and aberrant drainage. Lymphazurin 1% was injected subserosally around the tumor and 1-4 blue staining nodes were marked as SLNs for detailed histological analysis. SLN mapping was successful in 98% of patients with an average of 1.7 SLNs per patient. SLNs were negative in 63% of the patients and positive in 37% of the patients. Skip metastasis was seen in 8 of the patients. Occult micrometastasis was found in 14% of patients. In 5% of the patients, unusual lymphatic drainage lead to an alteration of the extent of lymphadenectomy. This multicenter trial proved that SLN mapping in patients with colorectal cancer is simple, cost effective, and upstages at least 14% of patients from AJCC stage I/II to stage III. These patients may then benefit from adjuvant chemotherapy.

Surgical resection for metastatic melanoma to the liver: the John Wayne Cancer Institute and Sydney Melanoma Unit experience.

HYPOTHESIS: Metastatic melanoma to the liver is not incurable; complete surgical resection can achieve long-term survival in selected patients. BACKGROUND: Metastases to the liver are diagnosed in 10% to 20% of patients with American Joint Committee on Cancer stage IV melanoma. Surgical resection has not been generally accepted as a therapeutic option, as most patients will have other sites of disease that limit their survival to a median of only 4 to 6 months. However, there is little information on outcomes following resection in those patients with disease limited to the liver. PATIENTS AND METHODS: Review of the prospective melanoma databases at the John Wayne Cancer Institute, Santa Monica, Calif, and the Sydney Melanoma Unit, Sydney, Australia, identified 1750 patients with hepatic metastases, of whom 34 (2%) underwent exploration with intent to resect the metastases. Prognostic factors within the group of patients who underwent resection were examined by univariate and multivariate analysis, and median disease-free survival (DFS) and overall survival (OS) were calculated. RESULTS: Of 34 patients undergoing exploratory celiotomy, 24 (71%) underwent hepatic resection and 10 (29%) underwent exploration but not resection. Eighteen patients (75%) underwent complete surgical resection, while the remaining 6 underwent palliative or debulking procedures with incomplete resection. The operative resections included lobectomy (n=14), segmentectomy (4), nonanatomic resection (5), and extended lobectomy (1). The median number of resected lesions was 1, and median lesion size was 5 cm (range, 0.7-22 cm). The median disease-free interval between initial diagnosis of melanoma and development of hepatic metastases was 58 months (range, 0-264 months). Median DFS and OS estimates in the 24 patients who underwent surgical resection were 12 months (range, 0-147 months) and 28 months (range, 2-147 months), respectively. Five-year DFS and OS in this group were 12% and 29%. Macroscopically, complete resection of disease (P =.001) and histologically negative resection margins (P =.03) significantly improved DFS by univariate analysis. Patients rendered surgically free of disease also tended to have improved OS (P =.06). Median OS was 28 months for patients who underwent surgical resection compared with 4 months for patients who underwent exploration only (P<.001). CONCLUSIONS: Resection of metastatic melanoma to the liver may improve DFS and OS in selected patients, similar to resection of other metastatic sites. Therefore, patients with limited metastatic sites, including the liver, who can be rendered free of disease should be considered for complete surgical resection, as their prognosis is otherwise dismal.

Diagnostic laparoscopy and laparoscopic ultrasonography optimize the staging and resectability of intraabdominal neoplasms.

BACKGROUND: Despite technical improvements, preoperative imaging studies often fail to predict intraoperative findings. We investigated the potential use of diagnostic laparoscopy (DL) and laparoscopic ultrasonography (LUS) for the assessment of disease in patients with abdominal neoplasms. METHODS: Fifty consecutive patients with abdominal neoplasms underwent spiral computed tomography with oral and intravenous contrast using 5-mm contiguous sections. In addition, eight patients underwent ultrasonography, six underwent magnetic resonance imaging, and eight underwent positron emission tomography. All patients then underwent DL and LUS using a 7.5-MHz ultrasound probe. RESULTS: There were 29 men and 21 women with a mean age of 63 years (range, 35-84). Most had a diagnosis of colorectal cancer (19 cases), melanoma (12 cases), or hepatoma (five cases). In nine cases (18%), DL revealed peritoneal metastatic implants not shown on preoperative images. In 18 cases (36%), LUS was more accurate than preoperative imaging. Combined DL and LUS findings radically changed the operative management in 16 patients (32%). CONCLUSION: As compared with preoperative imaging, the combination of DL and LUS provides more accurate information regarding staging and resectability. Moreover, it helps to determine the extent of operation and reduces the number of unnecessary laparotomies. DL and LUS should be used as an adjunct to preoperative imaging studies in patients with primary or metastatic intraabdominal neoplasms.

Laparoscopic radiofrequency ablation of unresectable hepatic malignancies. A phase 2 trial.

BACKGROUND: Radiofrequency ablation (RFA) of hepatic malignancies has been performed successfully via a percutaneous route or at laparotomy. We analyzed the efficacy and utility of laparoscopic intraoperative ultrasound and RFA in patients with unresectable hepatic malignancies. METHODS: Between November 1997 and November 1999, 27 patients with unresectable hepatic malignancies and no evidence of extrahepatic disease were entered in a phase 2 trial of laparoscopic intraoperative ultrasound and RFA. Real-time ultrasonography was used to guide RFA, and lesions were ablated at a temperature of 100 degrees C for 10 min. Overlapping ablations were performed for larger lesions. RESULTS: Additional tumors were identified in 10 (37%) of the 27 study patients by laparoscopy and laparoscopic intraoperative ultrasound despite extensive preoperative imaging. Radiofrequency ablation of 85 hepatic tumors yielded no mortality and only one case of postoperative bleeding. During a mean follow-up period of 14 months, four tumors (4.7%) locally recurred. Of the 27 patients, 11 (41%) remain free of disease at this writing; (22%) are alive with disease; and 10 (37%) have died with disease. CONCLUSION: Laparoscopic RFA and intraoperative ultrasound constitute a safe and accurate method for ablation of unresectable hepatic tumors.

CancerVax, an allogeneic tumor cell vaccine, induces specific humoral and cellular immune responses in advanced colon cancer.

BACKGROUND: The immunogenicity of the polyvalent tumor cell vaccine CancerVax has been correlated with the survival of patients receiving active immunotherapy for melanoma. Because the various antigens expressed on the vaccine are common to colon adenocarcinoma cells, we examined the survival impact of immune responses elicited by CancerVax in patients with advanced colon cancer refractory to standard therapy. METHODS: Twenty-seven patients with American Joint Committee on Cancer (AJCC) stage IV colorectal adenocarcinoma were entered prospectively into the study. CancerVax was coadministered with bacille Calmette-Guerin (BCG) for the first 2 weeks of vaccine treatment. Blood was drawn at the start of therapy and every 2 weeks thereafter to measure serum titers of immunoglobulin (Ig)G and IgM against TA90 (a 90-kD immunogen common to colon cancer and CancerVax cells) and against purified protein derivative (PPD), a nontumor control antigen. Cellular immune responses were evaluated by delayed-type hypersensitivity (DTH) reaction to vaccine cells and to PPD. Mean follow-up time was 17.5 months. RESULTS: There was a significant (P = .0001) increase in anti-TA90 IgG and IgM titers and in DTH response to vaccine cells. Humoral and skin responses to TA90 did not correlate with responses to PPD (P = .199 for IgM, P = .958 for IgG, and P = .149 for DTH). This suggests that these responses are not a manifestation of general immune competence. The median overall survival (OS) was 21.9 months for the entire group. Overall survival was higher among patients whose IgMTA90 titer was >800 (P = .003) or whose disease-free interval exceeded 12 months (P = .031). Multivariate Cox regression analysis-using age, sex, disease-free interval, disease status, extent of metastasis, humoral responses, and DTH responses-found only peak IgMTA90 titer to be a significant predictor of overall survival (P = .0365). CONCLUSIONS: CancerVax can induce measurable humoral and cellular immune responses to tumor-associated antigens in patients with advanced-stage colon cancer. These responses correlate with overall survival. This novel therapeutic regimen for patients with advanced colon cancer merits further investigation.

Interleukin-2 binds to ganglioside GD(1b).

We have developed a solid matrix immunoassay to determine the binding of interleukin-2 (IL-2) to specific gangliosides. The assay establishes that recombinant human IL-2 binds to ganglioside GD(1b) but not to any other gangliosides (GM(1), GM(2), GM(3), GD(1a), GD(2), GD(3), and GT(1b)). The binding varies with the ratio of GD1b and IL-2. This assay enables distinguishing the nature of the sugar moiety of the ganglioside recognized by IL-2 and establishes the dosimetry of the ganglioside-IL-2 interaction. Since rIL-2 is administered systematically into stage IV melanoma patients, we have examined 45 tumor biopsies for GD(1b) content. The incidence of GD(1b) in tumor biopsies is 51%. We postulate that GD(1b) associated on the tumor or in the circulation of cancer patients may bind to rIL-2 and prevent the availability of rIL-2 to augment antitumor-immune response.

Repeat hepatic cryotherapy for metastatic colorectal cancer.

This study evaluated the risks and benefits of repeat hepatic cryotherapy for recurrent, unresectable hepatic metastases from colorectal carcinoma. Review of a prospective database identified 195 patients who underwent hepatic cryotherapy for metastatic colorectal carcinoma during a 7-year period. Of the 14 patients who underwent successful repeat cryotherapy for recurrences confined to the liver, 86% had Duke's stage D colorectal carcinoma at initial diagnosis. The median age of the 14 patients was 58 years (range 41 to 77 years). The median number of hepatic metastases was three at the first cryotherapy and two at the second cryotherapy. At a median follow-up of 71 months, the mean survival times from original diagnosis, first cryotherapy, and second cryotherapy were 53, 42, and 19 months, respectively. At the most recent follow-up, eight patients (57%) have died of their disease, four (29%) are alive with disease, and two (14%) have no evidence of disease. The mean interval between the first and second cryotherapies was 23 months. The complication rates after the first and second cryotherapies were 7% and 14%, respectively. One patient developed a wound dehiscence after the first cryotherapy. Following the second cryotherapy, one patient had a small bowel obstruction and another had a pleural effusion. There was no perioperative mortality. Repeat cryotherapy for recurrent, unresectable hepatic metastases from colorectal cancer is safe and improves survival. However, a prospective trial is needed to validate the efficacy of systemic therapy and to better define the indications for repeat hepatic cryotherapy.

Validation of lymphatic mapping in colorectal cancer: in vivo, ex vivo, and laparoscopic techniques.

BACKGROUND: The use of lymphatic mapping (LM) is being investigated to improve the staging of colorectal cancer (CRC) and thereby identify patients who might benefit from adjuvant chemotherapy. This study evaluated in vivo, laparoscopic, and ex vivo approaches for the ultrastaging of CRC. METHODS: Seventy-five CRC patients were enrolled in a study of LM with peritumoral injection of isosulfan blue dye. LM was undertaken during open colon resection (OCR) in 64 patients, during laparoscopic colon resection (LCR) in 9 patients, and after specimen removal (ex vivo) in 2 patients. Ex vivo LM was also undertaken in 6 patients after unsuccessful in vivo LM. All nodes were examined by hematoxylin and eosin (H&E) staining; in addition, sentinel lymph nodes (SNs) were multisectioned and examined by immunohistochemical staining with cytokeratin (CK-IHC). RESULTS: At least one SN was identified in 72 patients (96%). In vivo LM identified SNs in 56 of 64 (88%) patients undergoing OCR and in 9 of 9 (100%) patients undergoing LCR. Ex vivo LM was undertaken as the initial mapping procedure in 2 cases of intraperitoneal colon cancer and after in vivo LM had failed in 6 cases of extraperitoneal rectal carcinoma; an SN was identified in 7 of the 8 cases. Focused examination of the SN correctly predicted nodal status in 53 of 56 OCR cases, 9 of 9 LCR cases, and 6 of 7 ex vivo cases. Multiple sections and CK-IHC identified occult micrometastases in 13 patients (17%), representing 10 OCR, 1 LCR, and 2 ex vivo cases. CONCLUSIONS: LM of drainage from a primary CRC can be accurately performed in vivo during OCR or LCR. Ex vivo LM can be applied when in vivo techniques are unsuccessful and may be useful for rectal tumors. During LCR, colonoscopic injection can be used to mark the primary tumor and define the lymphatic drainage so that adequate resection margins are obtained. These LM techniques improve staging accuracy in CRC.

Molecular strategy for detecting metastatic cancers with use of multiple tumor-specific MAGE-A genes.

BACKGROUND: The human melanoma-associated antigen family A (MAGE-A) has high specificity and expression in various malignancies, but individual family members are expressed at low frequency in any one particular type of cancer. We therefore developed a method to detect mRNAs from multiple MAGE-A genes in a single reaction. METHODS: Universal MAGE-A (uMAGE-A) primers and probe were designed to reverse-transcribe, amplify, and detect by electrochemiluminescence (ECL) MAGE-A mRNAs on the Origen Analyzer. The assay was performed on total RNA of melanoma (n = 9 cell lines and 24 tumors), breast cancer (n = 7 and 26), and colorectal cancer (CRC; n = 5 and 12). We also evaluated blood from melanoma (n = 50), breast cancer (n = 16), and CRC (n = 21) patients. RESULTS: The uMAGE-A mRNA was detectable in 0.01-1 ng of cell line RNA. The identity of the uMAGE-A cDNA products was confirmed by sequencing and polyacrylamide gel electrophoresis. The uMAGE-A assay increased detection of melanoma, breast cancer, and CRC tumor by 13%, 31%, and 25%, respectively, compared with a MAGE-A1 assay, and by 17%, 19%, and 25%, respectively, compared with a MAGE-A3 assay. The uMAGE-A assay detected circulating tumor cells in the blood of melanoma (24%), breast cancer (25%), and CRC (29%) patients. CONCLUSIONS: The uMAGE-A reverse transcription-PCR/ECL assay provides a practical and sensitive approach for detection of various metastatic cancers in tissues and blood.

Radiofrequency ablation of unresectable hepatic malignancies: lessons learned.

Radiofrequency ablation (RFA) is increasingly used for the local destruction of unresectable hepatic malignancies. Relative contraindications include tumors in proximity to vital structures that may be injured by RFA and lesions whose size exceeds the ablation capabilities of the probe system employed. Given current technology, we believe that RFA should be cautiously utilized for lesions greater than 5 cm in diameter. Open (celiotomy) and laparoscopic approaches to RFA allow intraoperative ultrasonography, which may demonstrate occult hepatic disease. In addition, RFA performed via celiotomy can be accompanied by resection or cryosurgical ablation, and isolation of the liver from adjacent organs. Percutaneous RFA should be reserved for patients who cannot undergo general anesthesia, those with recurrent or progressive lesions, and those with smaller lesions sufficiently isolated from adjacent organs. Complications may be minimized when these approaches are selectively applied.

Molecular staging of early colon cancer on the basis of sentinel node analysis: a multicenter phase II trial.

PURPOSE: Approximately 30% of patients with American Joint Committee on Cancer stage I or II colorectal cancer (CRC) develop systemic disease. We hypothesized that multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of sentinel lymph nodes (SNs) draining a primary CRC could detect micrometastases not detected by conventional histopathologic analysis. PATIENTS AND METHODS: In a multi-institutional study, 40 patients with primary CRC underwent dye-directed lymphatic mapping at the time of colon resection. Each dye-stained SN was tagged, and the tumor and regional nodes were resected en bloc. All lymph nodes were examined by conventional hematoxylin and eosin (HE) staining. In addition, each SN was cut into multiple sections for cytokeratin immunohistochemical (CK-IHC) staining and for RT-PCR and electrochemiluminescent detection of three markers: beta-chain human chorionic gonadotropin, hepatocyte growth factor receptor, and universal melanoma-associated antigen. Whenever possible, RT-PCR assay was also performed on primary tumor tissue. The detection sensitivity of individual markers was 10(-3) to 10(-4) microg of RNA and one to five tumor cells in 10(7) lymphocytes of healthy donors. RESULTS: One to three SNs were identified in each patient. An average of 15 nodes were removed from each CRC specimen. No nonsentinel (untagged) node contained evidence of tumor if all tagged (sentinel) nodes in the same specimen were histopathology tumor-negative. HE staining of SNs identified tumor in 10 patients (25%), and CK-IHC of SNs identified occult micrometastases in four patients (10%) whose SNs were negative by HE. Of the remaining 26 patients with no evidence of SN involvement by HE or CK-IHC, 12 (46%) had positive RT-PCR results. The number of markers expressed in each SN correlated (P <.04) with the T stage of the primary tumor. There was 79% concordance in marker expression for the respective pairs (n = 38) of primary tumor and histopathologically positive SNs, and 86% (12 of 14) concordance between RT-PCR positive and histopathologically positive SNs. CONCLUSION: Identification and focused examination of the SN is a novel method of staging CRC. CK-IHC and RT-PCR identified occult micrometastases in 53% of patients whose SNs were negative by conventional staging techniques. These ultrasensitive assays of the SN can identify patients who may be at high risk for recurrence of CRC and therefore are more likely to benefit from systemic adjuvant therapy.

Solid and papillary epithelial neoplasms of the pancreas: aggressive resection for cure.

Solid and papillary epithelial neoplasms of the pancreas (SPENP) are extremely rare and usually affect young women. We retrospectively reviewed our experience with pancreatic neoplasms from 1986 to the present and identified nine patients with SPENP. All nine patients were female with a mean age of 32 years (range 16-66). All patients presented with gastrointestinal complaints including pain, mass, dyspepsia, or bloating and were subsequently diagnosed with a tumor of the pancreas by CT scan. All patients underwent surgical resection. Two patients had tumors located in the head of the pancreas and underwent a pancreaticoduodenectomy. The remainder had tumors located in the tail of the pancreas and underwent distal pancreatectomy. Pathology demonstrated solid and papillary or solid and cystic pseudopapillary neoplasm of the pancreas. Three tumors were positive for both vimentin and alpha-1 antitrypsin on immunohistochemical studies, and three were positive for neuron-specific enolase. All nine patients underwent curative resection and are alive without any evidence of recurrence with a mean follow-up of 5.4 years. SPENP is considered to be a low-grade malignancy with an excellent prognosis. Prompt diagnosis and surgical resection can result in cure.