Nuclear medicine in the detection of the sentinel node.

Lymphoscintigraphy and radioguided surgery are valuable tools for contemporary surgical staging of malignancies, but they require attention to detail and a moderate level of experience for optimal clinical use. Wide use of these procedures has demonstrated that the methodology can be learned with guidance from a few dozen cases. Their accurate use significantly enhances the sentinel node technique.

Pathologic examination of sentinel lymph node for breast carcinoma.

Comprehensive pathologic evaluation of the sentinel lymph node using step sections and cytokeratin immunohistochemistry enhances detection of micrometastases and optimizes the staging of breast carcinoma. This review discusses our current understanding of the pathologic and molecular techniques for sentinel node examination.

Dermal versus intraparenchymal lymphoscintigraphy of the breast.

BACKGROUND AND OBJECTIVE: Dermal and intraparenchymal (IP) injections of radiocolloid have been used for lymphoscintigraphic identification of the sentinel node (SN) in breast cancer. Because of our institute's extensive experience with dermal and IP lymphoscintigraphy for melanoma and breast cancer, we compared patterns of lymphatic migration after both types of injections to identify any differences in drainage patterns or SN identification. METHODS: Lymphoscintigrams (n = 31) after dermal injections in 30 patients with primary cutaneous melanoma on the breast were compared with lymphoscintigrams after IP injections in 97 consecutive patients with breast cancer. In each case, 400 microCi of filtered 99mTc-sulfur colloid was injected in four quadrants around the tumor or in the biopsy cavity. All lymphoscintigrams were reviewed for patterns of migration and SN location. RESULTS: Five of 31 (16%) dermal injections demonstrated bilateral axillary migration (n = 3) or a suprasternal SN (n = 2), neither of which was found with IP injections. Conversely, 3 of 97 (3%) IP injections demonstrated direct supraclavicular (n = 2) or costal margin (n = 1) nodes (P = .006), neither of which was found with dermal injections. Low axillary SNs were noted after 26 (84%) dermal and 93 (96%) IP injections (P = .037). The incidence of extra-axillary SNs was 26% (8 of 31) in the dermal group but only 5% (5 of 97) in the IP group (P = .0027). CONCLUSION: There is a significant difference in lymphatic drainage and SN localization between dermal and IP lymphoscintigraphy. This finding has implications for injection techniques when lymphatic mapping of the SN is undertaken to stage a breast carcinoma.

Application of an [(18)F]fluorodeoxyglucose-sensitive probe for the intraoperative detection of malignancy.

BACKGROUND: Whole-body positron emission tomography (PET) has been shown to be a highly sensitive method for detecting malignancy not imaged by conventional modalities. We have adapted a hand-held gamma-ray-sensitive probe to detect the radiation emission from the [(18)F]fluorodeoxyglucose (FDG) used in PET imaging. This pilot study was devised to examine the feasibility of using a hand-held probe to intraoperatively differentiate normal from tumor-bearing tissue. MATERIALS AND METHODS: A commercially available gamma probe was adapted to detect the radioactivity released from FDG and examined to determine the in vitro sensitivity for localization of a FDG point source. Eight consecutive patients underwent resection of metastatic colon cancer or melanoma; each received a preoperative injection of 7--10 mCi of FDG. The gamma probe was used to determine radioactive counts per second from tumor and normal tissue, and ratios of tumor to adjacent normal background were calculated. RESULTS: In vitro studies with a FDG point source demonstrated the probe could identify the source with a 50% reduction in maximum counts 1.7 +/- 0.1 cm from the source (full-width half-maximum measurement). Based on the results of their preoperative PET scans 17 tumors were identified from the 8 patients. Of the 17 tumors assessed the in vivo tumor-to-background ratios varied from 1.16:1 to 4.67:1 for the melanoma patients (13 tumors) and from 1.19:1 to 7.92:1 for colon cancer patients (4 tumors). Thirteen tumors were resected; four (2 patients) were unresectable. CONCLUSIONS: This study demonstrates the use of a hand-held gamma-ray-sensitive probe to intraoperatively differentiate the radioactivity released from FDG from tumor-bearing and adjacent normal tissue. While further studies are necessary for us to optimize the use of this probe, the intraoperative detection of FDG-avid malignancies may ultimately improve our ability to completely resect patients with metastatic disease.

Factors affecting sentinel node localization during preoperative breast lymphoscintigraphy.

UNLABELLED: Variable success rates for identifying axillary (AX) sentinel nodes in breast cancer patients using preoperative lymphoscintigraphy have been reported. We evaluated the effects of age, weight, breast size, method of biopsy, interval after biopsy, and imaging view on the success of sentinel node identification and on the kinetics of radiopharmaceutical migration. METHODS: Preoperative breast lymphoscintigraphy was performed in consecutive breast cancer patients from February 1998 to December 1998. The ipsilateral shoulder was elevated on a foam wedge and the arm was abducted and elevated overhead. Imaging using this modified oblique view of the axilla (MOVA) started immediately after peritumoral injection of Millipore-filtered 99mTc-sulfur colloid and continued until AX sentinel nodes were identified. Anterior views were obtained after MOVA. AX, internal mammary (IM), and clavicular (CL) basins were monitored in all patients. MOVA was compared with the anterior view for sentinel node identification. Age, weight, breast size, method of biopsy, interval after biopsy, and primary tumor location were evaluated for their effects on sentinel node localization and transit times from injection to arrival at the sentinel nodes. RESULTS: Seventy-six lymphoscintigrams were obtained for 75 patients. AX sentinel nodes were revealed in 75 (99%) cases. IM or CL sentinel nodes were found in 19 (25%) cases and were not related to tumor location; exclusive IM drainage was present in 1 (1%) case. Identification of AX sentinel nodes was equivalent with MOVA and anterior views in 18 (24%) patients, was better with MOVA in 20 (26%) patients, and was accomplished only with MOVA in 38 (50%) patients. Median transit time was 17.5 min (range, 1 min to 18 h) after injection, and larger breast size was associated with increased transit time. No effect of age, weight, biopsy method, interval from biopsy, or tumor location on transit time was found. CONCLUSION: Use of MOVA can improve identification of AX sentinel nodes. Although AX drainage is the predominant pattern, a tumor in any portion of the breast can drain to IM sentinel nodes. Transit time was influenced by breast size. Overall short arrival times with this technique allow sentinel lymph node dissection to be performed on the same day as lymphoscintigraphy.

Pathologic features associated with nonsentinel lymph node metastases in patients with metastatic breast carcinoma in a sentinel lymph node.

BACKGROUND: To the authors' knowledge it has not yet been determined which patients with primary breast carcinoma and an axillary sentinel lymph node (SN) metastasis have additional metastases in nonsentinel lymph nodes. METHODS: Pathologic features of the primary breast carcinoma and its SN metastasis were examined in 194 patients and correlated with the tumor status of the non-SNs in the same axillary basin. Two-level cytokeratin immunohistochemistry was applied to the SNs and to non-SNs of cases that were negative by standard hematoxylin and eosin examination. RESULTS: Lymph node staging based on SN findings, size of the primary tumor, and presence of peritumoral lymphatic vascular invasion (LVI) were associated with non-SN metastasis. The majority (63%) of the 101 patients with SN macrometastases had non-SN metastases. Extranodal hilar tissue invasion in conjunction with SN involvement also was strongly associated with non-SN metastasis (P = 0.0001) but was present in only 65% of patients (35 of 54 patients) with non-SN macrometastases. Approximately 26% of patients (24 of 93 patients) with SN micrometastases (

Principles of sentinel lymph node identification: background and clinical implications.

The management of clinically negative regional lymph nodes in early-stage melanoma has been controversial for many years. While some advocate wide excision of the primary with elective node dissection (ELND), others recommend excision of the primary alone and therapeutic node dissection (TLND) for recurrences in the nodal basin. ELND is based on the concept that metastases occur by passage of the tumor from the primary to the regional nodes and distant sites, in which case early dissection of regional nodes will disrupt metastatic progression and prevent the spread of disease. Advocates of the "wait and watch" approach suggest that regional node metastases are markers for disease progression and that distant disease can occur without node metastases. Four randomized prospective studies comparing ELND and TLND have not demonstrated overall survival advantage for ELND, but suggest that patients with early regional metastases may benefit from ELND. As an alternative, Morton et al., from UCLA and the John Wayne Cancer Institute, devised intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL). These minimally invasive operative procedures allow identification of the first and key (sentinel) lymph node (SN). The technique accurately maps the lymphatics by lymphoscintigraphy, and vital blue dye leads the surgeon to the SN. The pathologist then concentrates on seeking metastases in the nodes most likely to contain metastases. Patients with tumor-positive SN undergo completion lymph node dissection (CLND), while those without SN metastases avoid the complications and costs associated with this procedure. Morton et al., in a report on their initial experience of LM/SL, performed CLND in all cases regardless of SN tumor status and demonstrated the precise staging capacity of the procedure. Since this initial report, numerous studies have validated the accuracy and low morbidity of the procedure. Each center must master a learning phase. The procedure is dependent on the close cooperation of nuclear medicine physicians, surgeons, and pathologists. While LM/SL is now almost standard practice in the US, the results of clinical trials are awaited to determine whether LM/SL can replace ELND and TLND in the management of early-stage melanoma.

Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer.

PURPOSE: Immediate complete axillary lymphadenectomy (ALND) after sentinel lymphadenectomy (SLND) has confirmed that tumor-negative sentinel nodes accurately predict tumor-free axillary nodes in breast cancer. Therefore, we hypothesized that SLND alone in patients with tumor-negative sentinel nodes would achieve axillary control, with minimal complications. PATIENTS AND METHODS: Between October 1995 and July 1997, 133 consecutive women who had primary invasive breast tumors clinically

Standardized probe-directed sentinel node dissection in melanoma.

BACKGROUND: Radiopharmaceutical agents appear to improve the accuracy of sentinel node (SN) identification in patients with early-stage melanoma, but the optimal radiopharmaceutical agent and its timing from injection to surgery remain controversial. We undertook this investigation to examine the utility of 3 methods of intraoperative lymphatic mapping with radiopharmaceutical-directed sentinel lymphadenectomy (LM/SL). We suspected that concurrent injection of radiopharmaceutical and blue-dye would lead to the greatest success of SN identification. METHODS: The study was composed of 247 consecutive patients who had American Joint Committee on Cancer stage I or II melanoma. Before LM/SL, all patients underwent cutaneous lymphoscintigraphy by 1 of 3 techniques: technetium 99m (Tc 99m) human serum albumin (HSA) injected at least 24 hours before LM/SL (124 patients), Tc 99m filtered sulfur colloid (SC) injected no more than 4 hours before LM/SL (same-day SC, 95 patients), or Tc 99m SC injected at least 18 hours before LM/SL (prior-day SC, 28 patients). At the time of LM/SL, isosulfan blue dye was injected alone (SC groups) or with a second dose of HSA (HSA group). A hand-held gamma probe was used to determine the radioactive (hot) counts of blue-stained and nonstained nodes, and the in vivo and ex vivo node-to-background count ratios of the nodes were compared. RESULTS: Preoperative LS identified 299 drainage basins; LM/SL identified at least 1 SN in 119 (98%) of 121 basins using same-day SC, 142 (97%) of 146 basins using HSA, and 32 (100%) of 32 basins using prior-day SC. There was no difference (P = .62) in the accuracy rate between the 3 techniques. The total number of SNs was 463. Same-day SC yielded higher intraoperative node-to-background count ratios than did either of the other techniques (P < .0001). Same-day SC also had the greatest relative change in radioactivity between the blue sentinel node and the post-excision basin (P < .0001), and the highest rate of SNs that were both blue and hot (in vivo or ex vivo ratio > or = 2, P = .05). CONCLUSIONS: LS and LM/SL performed on the same day with a single injection of filtered Tc 99m SC serves as the most useful method for probe-directed LM/SL. This technique demonstrated the highest in vivo and ex vivo count ratios, fall-off of radioactivity between the excised nodes and post-excision basin, and concordance between blue dye and hot nodes. It should be recommended as the method of choice for probe-directed LM/SL.

Accuracy of gamma probes in localizing radioactivity: in-vitro assessment and clinical implications.

BACKGROUND: Radioguided surgery (RGS) uses gamma probes to localize radioactive targets. We examined the in-vitro localizing properties of commercially available gamma probes for three common RGS radioisotopes: technetium-99m (99mTc), indium-111 (111In), and iodine-125 (125I). METHODS: The linear and angular localizing properties of five gamma probes were assessed. Radioactive counts in air were obtained at multiple energy threshold settings for each radioisotope. The full width half maximum (FWHM) and angular half maximum (AHM) were calculated to determine localizing accuracy. RESULTS: The FWHM of the five probes ranged from 1.2 to 3.4 cm for 99mTc, 1.8 to 2.7 cm for 111In and 1.6 to 2.8 cm for 125I. AHM of the probes ranged from 20 to 49 degrees for 99mTc, 14 to 35 degrees for 111In, and 18 to 47 degrees for 125I. The ranking of probe accuracy depended on the radioisotope studied. Absolute count rates varied with energy threshold settings for each probe and radioisotope. Probes required individualized energy threshold settings for optimal performance. CONCLUSIONS: The five probes varied in their characteristics for localizing the three radioisotopes. Each probe has particular detection characteristics that may change with different radioisotopes. Differences in radioisotope detection may explain intraoperative variation in localization during lymphatic mapping and sentinel lymph node dissection (LM/SL). Surgeons should be aware of probe performance characteristics before intraoperative use.

Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group.

OBJECTIVE: To evaluate the multicenter application of intraoperative lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection (LM/SL/SCLND) for the management of early-stage melanoma. SUMMARY BACKGROUND DATA: The multidisciplinary technique of LM/SL/SCLND has been widely adopted, but not validated in a multicenter trial. The authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT) 5 years ago to evaluate the survival of patients with early-stage primary melanoma after wide excision alone versus wide excision plus LM/SL/SCLND. This study examined the accuracy of LM/SL/SCLND in the MSLT, using the experience of the organizing center (John Wayne Cancer Institute [JWCI]) as a standard for comparison. METHODS: Before entering patients into the randomization phase, each center in the MSLT was required to finish a 30-case learning phase with complete nuclear medicine, pathology, and surgical review. Selection of MSLT patients in the LM/SL/SCLND treatment arm was based on complete pathologic and surgical data. The comparison group of JWCI patients was selected using these criteria: primary cutaneous melanoma having a thickness > or =1 mm with a Clark level > or =III, or a thickness <1 mm with a Clark level > or =IV (MSLT criterion); LM/SL performed between June 1, 1985, and December 30, 1998; and patient not entered in the MSLT. The accuracy of LM/SL/SCLND was determined by comparing the rates of sentinel node (SN) identification and the incidence of SN metastases in the MSLT and JWCI groups. RESULTS: There were 551 patients in the MSLT group and 584 patients in the JWCI group. In both groups, LM performed with blue dye plus a radiocolloid was more successful (99.1 %) than LM performed with blue dye alone (95.2%) (p = 0.014). After a center had completed the 30-case learning phase, the success of SN identification in the MSLT group was independent of the center's case volume or experience in the MSLT. CONCLUSIONS: Lymphatic mapping and sentinel lymphadenectomy can be successfully learned and applied in a standardized fashion with high accuracy by centers worldwide. Successful SN identification rates of 97% can be achieved, and the incidence of nodal metastases approaches that of the organizing center. A multidisciplinary approach (surgery, nuclear medicine, and pathology) and a learning phase of > or =30 consecutive cases per center are sufficient for mastery of LM/SL in cutaneous melanoma. Lymphatic mapping performed using blue dye plus radiocolloid is superior to LM using blue dye alone.

Sentinel node localization in breast cancer.

The status of the axillary nodes is the strongest known prognostic variable in patients with early breast cancer, and is routinely used in planning postoperative therapy. Conventional axillary lymph node dissection is limited by sampling error and potential morbidity. Sentinel node techniques have revolutionized the management of axillary nodes. Accurate identification and focused histologic evaluation of the sentinel node allow accurate prediction of the tumor status of other axillary nodes, thereby avoiding the morbidity and expense of a complete axillary dissection in node-negative patients. Radiotracer techniques play an important role in the preoperative and intraoperative localization of the sentinel nodes. Optimal localization of the sentinel node requires the use of both preoperative lymphoscintigraphy and intraoperative radiosensitive probes. Lymphoscintigraphy also identifies patients with lymphatic drainage to sites other than the axilla, thereby allowing more appropriate treatment and follow-up in this subset of patients. Procedures for localizing sentinel nodes require an understanding of the kinetics of the radiopharmaceuticals or other tracers used and the detection devices employed in each institution. Both surgical and nuclear medicine personnel should understand these principles, and close cooperation between surgeons, nuclear medicine physicians, and pathologists is essential for the application of sentinel node techniques.

Positron emission tomography plus serum TA90 immune complex assay for detection of occult metastatic melanoma.

BACKGROUND: Whole-body positron emission tomography (PET) using 18F-fluorodeoxyglucose is very sensitive for detection of metastatic melanoma. We previously reported the accuracy of a serum TA90 enzyme-linked immunosorbent assay (ELISA) in predicting the recurrence of early-stage melanoma. This serum ELISA measures a circulating immune complex composed of TA90 a tumor-associated 90-kD glycoprotein antigen, and its IgG antibody. We hypothesized that using PET examination in conjunction with our serum TA90 ELISA would increase the detection of occult melanoma lesions. STUDY DESIGN: From November 1, 1993 to December 31, 1995, 87 patients underwent PET examination followed within 6 weeks by serum TA90 ELISA. All patients had undergone complete resection of local, regional, or distant metastatic melanoma and had no clinical evidence of disease at the time of PET examination. Each patient had complete followup for 12 months after PET examination. The clinical course was determined by chart review of clinical and radiographic findings. RESULTS: Of the 25 patients who experienced recurrence of disease within 6 months of followup, 22 (88%) had a positive result on one or both tests. Of the 52 patients with a negative result on both tests, 49 (94%) remained disease-free at 6 months of followup. Of the 14 patients who developed distant metastases within 6 months after PET examination, 13 (93%) had a positive PET examination and/or a positive TA90 ELISA. CONCLUSIONS: The TA90 ELISA correlated well with PET examination for detection of metastatic melanoma. The high sensitivity of PET examination plus TA90 ELISA suggests that this combination may have a role in the surveillance of patients at high risk of developing metastatic melanoma.

Kinetics of three lymphoscintigraphic agents in patients with cutaneous melanoma.

UNLABELLED: Although lymphoscintigraphy is commonly used for the preoperative evaluation of patients with cutaneous melanoma and for intraoperative identification of sentinel lymph nodes, there is no consensus regarding the most useful radiopharmaceuticals or imaging times. METHODS: Fifty-one consecutive patients with clinical American Joint Committee on Cancer Stage I or II melanoma were assigned to one of three groups of 17 for lymphoscintigraphy with one of three radiopharmaceuticals: 99mTc-albumin colloid (AC), 99mTc-human serum albumin (HSA) or 99mTc-sulfur colloid (SC). Colloidal agents were filtered through 0.2 microm filters. After injecting 18.5-30 MBq (500-800 microCi) of the radiopharmaceutical, dynamic monitoring over injection sites and node basins was performed to identify draining lymphatic channels and sentinel nodes. In addition, static digital and analog images were acquired from the injection site and draining node basins immediately after injection and at 30 min (early) and 2 to 4 hr (delayed) after injection. Dynamic and static images were analyzed to determine transit times to the sentinel node, the number of nodes visualized in early and delayed images, the quality of lymph node and lymph channel visualization, the sentinel-to-nonsentinel uptake ratios and the washout rates from injection sites. RESULTS: Early images with all three agents provided reliable identification of sentinel lymph nodes. Technetium-99m-HSA demonstrated faster washout rates from injection sites and better definition of lymph channels than either particulate agent, whereas particulate agents were retained longer in nodes and demonstrated more nodes in delayed images than in early images. All agents demonstrated lymph channels better in early images than in delayed images. In general, variations between patients exceeded differences between agents. Sentinel nodes could not be distinguished reliably from nonsentinel nodes in delayed images alone. CONCLUSION: All three agents are acceptable for cutaneous lymphoscintigraphy, but reliable identification of sentinel nodes and their afferent lymph channels requires early imaging. Delayed imaging or localization alone is unreliable and may lead to incorrect identification of the sentinel node.

PET scans of abdominal malignancy.

Positron emission tomography (PET) with fluorine-18-2-d-deoxyglucose (FDG) currently is being integrated into clinical oncology because it provides unique functional information that can be applied to the management of cancer. In particular, it is useful for assessing tumor activity and growth, evaluating efficacy of therapy, and detecting tumor recurrence. Studies have demonstrated the value of whole-body PET-FDG imaging when staging and managing abdominal malignancy.

The lung as a metabolic organ.

Recently, the lung has received increasing attention as a metabolic organ. In this role, the lung modulates the composition of the arterial blood by several mechanisms: removing active substances from the plasma, releasing substances into the plasma, temporarily holding substances from circulation, and activating or inactivating substances that pass through the lungs. In this report, the procedures proposed by different investigators for in vivo noninvasive assessment of the lung metabolic functions are reviewed. Most procedures are based on an estimation of the clearance of plasma amines by the lung endothelial cells. This clearance is assessed by measuring the lung uptake or the extraction fraction of an intravenously (IV) injected radiolabeled amine. Our own procedure, which assesses the number of free pulmonary endothelial amine receptors, is discussed in detail. In our procedure, the number of receptors was computed using the number of injected molecules of amine and determining the lung extraction fraction of the amine during its first pass through the lungs. In goats, using N-isopropyl-p-iodoamphetamine labeled with 123I as the radiopharmaceutical, the total number of endothelial lung amine receptors was found to be 1.589 X 10(20). The methods for studying the lung metabolic functions, which are discussed in this report can be applied in humans to evaluate either physiological or pathological conditions.