Impact of rapid genetic counselling and testing on the decision to undergo immediate or delayed prophylactic mastectomy in newly diagnosed breast cancer patients: findings from a randomised controlled trial.

BACKGROUND: Female breast cancer patients with a BRCA1/2 mutation have an increased risk of contralateral breast cancer. We investigated the effect of rapid genetic counselling and testing (RGCT) on choice of surgery. METHODS: Newly diagnosed breast cancer patients with at least a 10% risk of a BRCA1/2 mutation were randomised to an intervention group (offer of RGCT) or a control group (usual care; ratio 2 : 1). Primary study outcomes were uptake of direct bilateral mastectomy (BLM) and delayed contralateral prophylactic mastectomy (CPM). RESULTS: Between 2008 and 2010, we recruited 265 women. On the basis of intention-to-treat analyses, no significant group differences were observed in percentage of patients opting for a direct BLM (14.6% for the RGCT group vs 9.2% for the control group; odds ratio (OR) 2.31; confidence interval (CI) 0.92-5.81; P=0.08) or for a delayed CPM (4.5% for the RGCT group vs 5.7% for the control group; OR 0.89; CI 0.27-2.90; P=0.84). Per-protocol analysis indicated that patients who received DNA test results before surgery (59 out of 178 women in the RGCT group) opted for direct BLM significantly more often than patients who received usual care (22% vs 9.2%; OR 3.09, CI 1.15-8.31, P=0.03). INTERPRETATION: Although the large majority of patients in the intervention group underwent rapid genetic counselling, only a minority received DNA test results before surgery. This may explain why offering RGCT yielded only marginally significant differences in uptake of BLM. As patients who received DNA test results before surgery were more likely to undergo BLM, we hypothesise that when DNA test results are made routinely available pre-surgery, they will have a more significant role in surgical treatment decisions.

Lymphoscintigraphy and SPECT/CT in multicentric and multifocal breast cancer: does each tumour have a separate drainage pattern? Results of a Dutch multicentre study (MULTISENT).

PURPOSE: To investigate whether lymphoscintigraphy and SPECT/CT after intralesional injection of radiopharmaceutical into each tumour separately in patients with multiple malignancies in one breast yields additional sentinel nodes compared to intralesional injection of the largest tumour only. METHODS: Patients were included prospectively at four centres in The Netherlands. Lymphatic flow was studied using planar lymphoscintigraphy and SPECT/CT until 4 h after administration of (99m)Tc-nanocolloid in the largest tumour. Subsequently, the smaller tumour(s) was injected intratumorally followed by the same imaging sequence. Sentinel nodes were intraoperatively localized using a gamma ray detection probe and vital blue dye. RESULTS: Included in the study were 50 patients. Additional lymphatic drainage was depicted after the second and/or third injection in 32 patients (64%). Comparison of planar images and SPECT/CT images after consecutive injections enabled visualization of the number and location of additional sentinel nodes (32 axillary, 11 internal mammary chain, 2 intramammary, and 1 interpectoral. A sentinel node contained metastases in 17 patients (34%). In five patients with a tumour-positive node in the axilla that was visualized after the first injection, an additional involved axillary node was found after the second injection. In two patients, isolated tumour cells were found in sentinel nodes that were only visualized after the second injection, whilst the sentinel nodes identified after the first injection were tumour-negative. CONCLUSION: Lymphoscintigraphy and SPECT/CT after consecutive intratumoral injections of tracer enable lymphatic mapping of each tumour separately in patients with multiple malignancies within one breast. The high incidence of additional sentinel nodes draining from tumours other than the largest one suggests that separate tumour-related tracer injections may be a more accurate approach to mapping and sampling of sentinel nodes in patients with multicentric or multifocal breast cancer.

In-transit lymph node metastases in breast cancer: a possible source of local recurrence after Sentinel Node procedure.

AIMS: In-transit lymph node metastases are a common phenomenon in melanoma patients and have been increasingly recognised since the introduction of the Sentinel Node (SN) procedure. To which extent this also occurs in patients with breast cancer has not been studied yet. The aim of this study was therefore to explore the occurrence of in-transit lymph node metastases in patients with breast cancer. METHODS: Afferent lymph vessels to the SN identified by blue dye were removed from 17 patients with breast cancer during a regular SN procedure. RESULTS: Three out of 17 patients showed a lymph node associated with the afferent lymph vessel. One of these lymph nodes showed a breast cancer macrometastasis, to be regarded as an in-transit metastasis. This metastasis would normally have been left in situ. CONCLUSIONS: In-transit lymph nodes associated with the afferent SN lymph vessels seem to occur in a significant proportion of patients with breast cancer. These lymph nodes may contain metastases, which are a potential source of local recurrence when left in situ. This finding generates the hypothesis that there may be an indication to remove these lymph vessels during the SN procedure.

Sentinel node investigation in breast cancer: detailed analysis of the yield from step sectioning and immunohistochemistry.

AIMS: To evaluate in detail the extent to which step sectioning and immunohistochemical examination of sentinel lymph nodes (SNs) in patients with breast cancer reveal additional node positive patients, to arrive at a sensitive yet workable protocol for histopathological SN examination. METHODS: This study comprised 86 women with one or more positive SN after a successful SN procedure for clinical stage T1-T2 invasive breast cancer. SNs were lamellated into pieces of approximately 0.5 cm in size. One initial haematoxylin and eosin (H&E) stained central cross section was made for each block. When negative, four step ribbons were cut at intervals of 250 microm. One section from each ribbon was stained with H&E, and one was used for immunohistochemistry (IHC). RESULTS: When taking the cumulative total of detected metastases at level 5 as 100%, the percentage of SN positive patients increased from 80%, 83%, 85%, 87% to 88% in the H&E sections through levels 1 to 5, and with IHC these values were 86%, 90%, 94%, 98%, and 100%. Three of nine patients in whom metastases were detected at levels 3-5 only had metastases in the subsequent axillary lymph node dissection. CONCLUSIONS: Multiple level sectioning of SNs (five levels at 250 microm intervals) and the use of IHC detects additional metastases up to the last level. Although more levels of sectioning might increase the yield even further, this protocol ensures a reasonable workload for the pathologist with an acceptable sensitivity when compared with the published literature.

Reliability of the sentinel node procedure in melanoma patients: analysis of failures after long-term follow-up.

BACKGROUND: The sentinel node (SN) concept assumes that early lymphatic metastases, if present, always are found first in the SN. The aim of this study was to determine the reliability of this procedure by establishing the success rate and number of failed procedures during a follow-up period of at least 2 years. METHODS: From August 1993 to November 1996, 204 consecutive patients with stage I and II cutaneous melanoma underwent SN biopsy by a triple technique. Preoperatively, all patients underwent (dynamic) lymphoscintigraphy. A gamma probe and blue dye helped localize the SN(s) during surgery, and these nodes subsequently were excised. These lymph nodes were step-sectioned and examined by routine and immunohistochemical staining. If the SN contained tumor cells, a lymphadenectomy was performed at a later date. RESULTS: The median follow-up time was 42 months. The success rate was 99%. Three patients developed a recurrence in the negative SN basin during follow-up, without simultaneous appearance of (locoregional) metastases. CONCLUSIONS: With a 99% success rate and a 1.5% rate of failed SN procedures (7% false-negative rate) after a median follow-up of 3.5 years, we concluded that the combined triple technique approach of detecting the SN was a reliable method to accurately identify and retrieve the SN.

Functional lymphatic anatomy for sentinel node biopsy in breast cancer: echoes from the past and the periareolar blue method.

OBJECTIVE: To simplify and improve the technique of axillary sentinel node biopsy, based on a concept of functional lymphatic anatomy of the breast. SUMMARY BACKGROUND DATA: Because of their common origin, the mammary gland and its skin envelope share the same lymph drainage pathways. The breast is essentially a single unit and has a specialized lymphatic system with preferential drainage, through select channels, to designated (sentinel) lymph nodes in the lower axilla. METHODS: These hypotheses were studied by comparing axillary lymph node targeting after intraparenchymal peritumoral radiocolloid (detected by a gamma probe) with the visible staining after an intradermal blue dye injection, either over the primary tumor site (90 procedures) or in the periareolar area (130 procedures). The radioactive content, blue coloring, and histopathology of the individual lymph nodes harvested during each procedure were analyzed. RESULTS: Radiolabeled axillary nodes were identified in 210 procedures, and these were colored blue in 200 cases (94%). The targeting concordance between peritumoral radiocolloid and intradermal blue dye was unrelated to the breast tumor location or the site of dye injection. Radioactive sentinel nodes were not stained blue in 10 procedures (5%), but this mismatching could be explained by technical problems in all cases. In two cases (1%), the (pathologic) sentinel node was blue but had no detectable radiocolloid uptake. CONCLUSIONS: The lessons learned from this study provide a functional concept of the breast lymphatic system and its role in metastasis. Anatomical and clinical investigations from the past strongly support these views, as do recent sentinel node studies. Periareolar blue dye injection appears ideally suited to identify the principal (axillary) metastasis route in early breast cancer. Awareness of the targeting mechanism and inherent technical restrictions remain crucial to the ultimate success of sentinel node biopsy and may prevent disaster.

Vital dye and radiolabelled colloids--complement or alternative?

Several different protocols for retrieval of the sentinel node (SN) have been described: gamma probe (GP) and/or dye guided biopsy, preceded by lymphoscintigraphy or not. Especially in American studies, predominantly executed by surgeons, dye or GP guidance only is used with good results. The disadvantages of applying dye only are: an extensive learning curve, lower retrieval rate of the SN and, especially in the learning phase, a higher rate of false negative biopsies. If only GP guidance is applied, the technique seems more simple to master. A recent multicentre study, however, revealed an unacceptably high false negative rate. It must be considered that most published studies were executed by highly experienced surgeons. In most European studies, scintigraphy is a standard part of the procedure. Lymphoscintigraphy provides the surgeon with a "road map", revealing the number and approximate location of the SNs in the lymphatic basin(s). Scintigraphy proves useful especially if an SN is situated close to the injection site (breast cancer), or if SNs are situated at unexpected locations (head-and-neck or trunk melanoma). A combination of all three available steps results in the highest number of successful procedures with the lowest false negative rate. This may prove to be especially important for general hospitals where the number of biopsy procedures is often smaller compared to specialized centres.

[Thoracoscopic clipping of thoracic duct in a woman with persisting chylothorax]. / Thoracoscopisch clippen van de ductus thoracicus bij een patiënte met persisterende chylothorax.

A 78-year-old female had chest pain, radiating to the back, caused by a thoracic aneurysm of the aorta. A vascular prosthesis was sutured into place through a left-sided thoracotomy. Six days after the operation she developed chylothorax on the right side. Following 14 days of conservative management, chyle leakage persisted at a rate of 1500 ml per 24 hours. By thoracoscopy the thoracic duct was dissected and clipped, which stopped the chyle leakage. The patient recovered moderately well. Conservative measures, such as adjusted nutrition, are successful in 50% of patients. Clipping of the thoracic duct by thoracoscopy is a definitive and minimally invasive procedure to treat persistent chyle leakage.

Ultrasound-guided lumpectomy of nonpalpable breast cancers: A feasibility study looking at the accuracy of obtained margins.

BACKGROUND AND OBJECTIVES: Complete excision of a nonpalpable breast cancer after wire localization is a difficult procedure. Often, adequate margins are not obtained, and a second procedure is then required. Prospectively, we studied the feasibility of ultrasound-guided excisions of nonpalpable breast cancers, with particular attention to the accuracy of the procedure in obtaining adequate margins. METHODS: Prospectively, 19 patients with 20 mammographically detected nonpalpable, highly suspect, breast tumors were entered in this feasibility study. In 15 of these, the diagnosis of invasive malignancy was established preoperatively. All patients underwent ultrasound-guided excision with the intent to obtain adequate margins. We also reviewed our own experience with the excision of nonpalpable breast cancers after wire localization. RESULTS: Of the 20 excisions with ultrasound guidance, there were 19 carcinomas and 1 ductal carcinoma in situ. Of the 19 carcinomas, 17 (89%) were excised with adequate margins. Of the 43 carcinomas that were excised after wire localization, only 17 (40%) had been resected with adequate margins. CONCLUSIONS: Ultrasound-guided excision appears to be a reliable procedure for obtaining adequate margins in the resection of nonpalpable breast cancers. Other advantages of this procedure are increased patient comfort and decrease in operating room time.

Selection of patients for resection of colorectal metastases to the liver using diagnostic laparoscopy and laparoscopic ultrasonography.

OBJECTIVE: To assess the value of diagnostic laparoscopy (DL) and laparoscopic ultrasonography (LUS) in the staging and selection of patients with colorectal liver metastasis. SUMMARY BACKGROUND DATA: Preoperative imaging modalities such as ultrasound, computed tomography, and magnetic resonance imaging are limited in the assessment of the number and exact location of hepatic metastases and in the detection of extrahepatic metastatic disease. Consequently, the surgeon is often faced with a discrepancy between preoperative imaging results and perioperative findings, resulting in either a different resection than planned or no resection at all. METHODS: Fifty consecutive patients were planned for DL and LUS in a separate surgical sitting to assess the resectability of their liver metastases. All patients were considered to be candidates for resection on the basis of preoperative imaging studies. RESULTS: Laparoscopy could not be performed in 3 of the 50 patients because of dense adhesions. The remaining 47 patients underwent DL. On the basis of DL and LUS, 18 (38%) patients were ruled out as candidates for resection. Of the 29 patients who subsequently underwent open exploration and intraoperative ultrasonography, another 6 (13%) were deemed to have unresectable disease. CONCLUSIONS: The combination of DL and LUS significantly improves the selection of candidates for resection of colorectal liver metastases and effectively reduces the number of unnecessary laparotomies.

Reliability of intraoperative frozen section and imprint cytological investigation of sentinel lymph nodes in breast cancer.

AIMS: The sentinel lymph node procedure enables selective targeting of the first draining lymph node, where the initial metastases will form. A negative sentinel node (SN) predicts the absence of tumour metastases in the other regional lymph nodes with high accuracy. This means that in the case of a negative SN, regional lymph node dissection is no longer necessary. Besides saving costs, this will prevent many side-effects of lymph node dissection. The aim of this study was to evaluate the reliability of intraoperative cytological and frozen section investigation of the SN to detect metastases. This would allow the axillary lymph node dissection to be performed in the same session as the SN procedure and the excision of the primary tumour in case of a positive SN. METHODS AND RESULTS: Seventy-four SNs were detected by gamma probe detection of nanocolloid and visual localization of Patent Blue accumulations in 54 women with stage T1-2N0M0 invasive breast cancer. The identified SN were immediately investigated by frozen section and imprint cytological investigation. Diagnoses were confirmed on the paraffin material, and in case of negative frozen section and paraffin haematoxylin and eosin sections, skip sections and immunohistochemistry were performed. Thirty-one SNs (42%) contained metastases, of which 27 were detected by the frozen section procedure (sensitivity 87%). There were no false positives (specificity 100%). The sensitivity of the imprints was 62% with a specificity of 100%. When evaluating the data per patient, for the frozen section procedure the sensitivity was 91% and the specificity 100%, and for the imprints, the sensitivity was 63% and the specificity 100%. There were no SNs in which the imprints showed metastases and the frozen section did not. CONCLUSIONS: Intraoperative frozen section analysis is a reliable procedure by which a high percentage of sentinel lymph node metastases can be detected in breast cancer patients without false positive results. This allows the surgeon to perform an immediate axillary lymph node dissection in case of positive SNs. In up to 10% of cases, the final paraffin sections will reveal micrometastases that were not detected by the frozen section, and in these patients axillary lymph node dissection will have to be performed in a second session. The imprint method is significantly less sensitive than the frozen section but may be used as an alternative when frozen section is not possible.

[Follow-up after melanoma resection is more extensive than recommended in the practice guidelines, primarily for reassurance of the patient]. / Follow-up na melanoomverwijdering uitgebreider dan aanbevolen in de consensus, ter geruststelling van de patiënt.

OBJECTIVE: To determine to what extent the follow-up after resection of melanoma in practice corresponds to the relevant guidelines in the first revised version of the consensus 'Melanoma of the skin'. DESIGN: Descriptive, retrospective. METHOD: For 67 patients, who had a melanoma resected in September 1993-April 1995 in the Academic Hospital, Vrije Universiteit, Amsterdam, the Netherlands, data were collected in May-August 1997 on the first two years of follow-up from the medical records (n = 42) and through communication in writing with the referring physicians and the physicians involved in the follow-up in other hospitals in the Netherlands (n = 25). The frequency of physical examination and routine diagnostics by the doctor was evaluated. To gain insight into the reasons why in some cases the guidelines were not followed, we set up an inquiry among the 20 doctors involved in the follow-up in August 1998. RESULTS: The mean frequency of outpatient visits and physical examinations was 3-4 times per year, practically consistent with the guideline. Routine blood testing was performed in 17 patients (25%) and diagnostic imaging (X-ray or CT scan of the chest, ultrasonography of the liver) in 51 patients (76%) in deviation from the guideline. Non-compliance with the guideline could not be explained by unfamiliarity with the consensus, disagreement with the contents or existence of local protocols. Extra diagnostics were mostly meant to reassure patients. No metastases or recurrences were encountered during routine follow-up examinations, but some were found (in 8 patients) at interim visits to the outpatient clinic. CONCLUSION: The national guidelines regarding diagnostic tests in the follow-up of melanoma patients are insufficiently followed. Because redundant routine diagnostics probably have more disadvantages than benefits, a more active implementation of (future) guidelines appears necessary.

Are locoregional cutaneous metastases in melanoma predictable?

BACKGROUND: In-transit metastases and satellite lesions are manifestations of locoregional cutaneous recurrence that are characteristic of malignant melanoma. They are the result of tumor cell emboli entrapped in the dermal lymphatics between the primary tumor and the regional lymph node basin. Histopathological features of lymphatic invasion were investigated to determine the possibility of predicting locoregional cutaneous metastases in melanoma patients. METHODS: In a prospective study, 258 patients with clinical stage I melanoma underwent wide local excision and sentinel node biopsy. Nodal metastases were found in 53 (21%) patients. Of 29 patients (11.2%) who had developed recurrences to date, 17 (6.6%) had locoregional cutaneous metastases. All surgical specimens were examined with particular attention to histopathological signs of lymphatic vascular invasion or microscopic satellites. RESULTS: Unequivocal signs of lymphatic invasion were observed in 14 of 258 patients (5.4%), and 13 (93%) of these patients subsequently developed in-transit metastases, after a median interval of 10 months. The primary melanoma was located on the extremities in seven patients. The median Breslow thickness was 2.5 mm, and 5 showed ulceration. In 244 of 258 patients (94.6%), there were no signs of lymphatic invasion. To date, only four patients (1.6%) have had a locoregional cutaneous recurrence, occurring after a median interval of 29 months. All four of these patients had ulcerative melanomas on an extremity, with a median thickness of 4.0 mm. The presence of lymphatic invasion was significantly related to early locoregional cutaneous relapse (P < .0001). CONCLUSIONS: Locoregional cutaneous recurrence appears to be highly predictable in the presence of histopathological signs of lymphatic invasion. Lymphatic invasion is an important prognostic parameter and should be included as a stratification criterion when selecting patients for adjuvant (locoregional) therapy.

Pathological investigation of sentinel lymph nodes.

The sentinel lymph-node procedure enables selective targeting of the first draining lymph node, where the initial metastases will form. A negative sentinel node (SN) predicts the absence of tumour metastases in the other regional lymph nodes with high accuracy. This means that in the case of a negative SN, regional lymph-node dissection is no longer necessary. Besides saving costs, this will prevent many side-effects as a result of lymph-node dissection. The task of the pathologist is to screen SNs for metastases. To this end, several techniques are available such as standard histo- and cytopathological techniques, immunohistochemistry, flow cytometry, and molecular biological techniques. These methods are explained and their sensitivity for detecting SN metastases is discussed. Some of these techniques also appear to be useful for intra-operative evaluation of SNs. The standard protocol for detection of SN metastases consists of extensive histopathological investigation including step H&E stained sections and immunohistochemistry. Intra-operative frozen-section analysis of SNs has been shown to be reliable for breast-cancer axillary lymph nodes. In the intra-operative setting, imprint cytology can also be used but its additional value to frozen section analysis is not yet clear. Further studies are necessary to establish the role of sophisticated molecular biological techniques such as reverse transcription polymerase chain reaction (RT-PCR) in detecting SN metastases. The sensitivity of flow cytometry is too low for this purpose.

Transport and retention of colloidal tracers in regional lymphoscintigraphy in melanoma: influence on lymphatic mapping and sentinel node biopsy.

Sentinel node (SN) biopsy is a staging technique used to select patients for regional lymphadenectomy in melanoma. We compared the two most widely used radioactive tracers, 99mTc-colloidal albumin (99mTc-CA) and 99mTc-sulphur colloid (99mTc-SC), with respect to scintigraphy, success rate in gamma probe guided biopsy and absolute uptake in the SN. Scintigraphy was performed in six volunteers after simultaneous injection of the respective tracers in each leg. Comparison of uptake of both tracers showed a higher uptake on the 99mTc-CA side. The scintigraphic count ratio of SNs labelled with 99mTc-SC compared with 99mTc-CA was 1 to 9 28. Next, 20 patients with biopsy-proven melanoma were randomized for injection of 99mTc-CA or 99mTc-SC followed by SN biopsy. Within 20 min after the injection, focal uptake was seen in all cases of the 99mTc-CA group but in only seven of the 10 patients in the 99mTc-SC group (P < 0.05). Focal accumulations were seen in all patients of both groups after 2 h. Spill to non-SNs was seen in five of the 99mTc-CA patients and three of the 99mTc-SC patients. In all patients the SNs could be retrieved under the guidance of a gamma probe and blue dye. The uptake in the SN was significantly higher (P < 0.001) after the injection of 99mTc-CA (0.92+/-0.40%) compared with 99mTc-SC (0.34+/-0.34%). When dynamic scintigraphy is performed, 99mTc-CA is preferable. SN uptake of 99mTc-SC is less than that of 99mTc-CA but this does not adversely affect the surgical procedure.