[Regional lymph nodes at a distance]. / Regionale lymfekliergebieden op afstand.

In 3 patients, two men aged 22 years and 38 years with melanoma, and one woman aged 46 years with breast cancer, local tumour growth recurred following regional lymph node dissection. All three developed metastasis in new distant regional basins, which were once more dissected. The first melanoma patient died from haematogenous metastasis, 2 years after the excision of his primary melanoma. The other melanoma patient was alive, without evidence of disease, 8 years after the treatment of his primary tumour. The breast cancer patient, who underwent contralateral axillary lymph node dissection, was also alive, without evidence of disease, 27 years after the treatment of her primary tumour. Diversion of lymphatic flow as a result of regional lymph node dissection for cancer may lead to metastasis to a distant lymph node basin if tumour growth recurs in the original area. Knowledge of this usually unknown phenomenon is important since metastasis to these new regional basins can still be treated curatively, in the form of another lymph node dissection. These distant lymph node basins must therefore be carefully checked during follow-up monitoring.

Value of serum S-100B for prediction of distant relapse and survival in stage III B/C melanoma.

BACKGROUND: The biochemical marker serum S-100B has been proven to reflect the stage of melanoma and to be useful for disease monitoring and prediction of survival, mainly in stage IV disease. For stage III melanoma, limited data are available and its predictive value for relapse is unknown. Serum S-100B was evaluated prospectively for monitoring response and its predictive value for relapse and overall survival in stage IIIB/C melanoma patients. PATIENTS AND METHODS: Treatment consisted of one cycle of neoadjuvant and adjuvant chemo(immuno)therapy, around surgery. S-100B was measured at enrollment and prior to and following surgery. The levels of S-100B in serum were compared to the pattern and intensity of the expression of S-100B in the melanoma tissue. RESULTS: Some patients with normal initial S-100B values (n=18) showed responses (3 complete remission and 2 partial remission), in contrast to patients with elevated S-100B values. Distant relapse within one year was found in 11/23 (48%) patients with increased S-100B versus 2/18 (11%) patients with a normal value (p=0.01). Overall survival was decreased in patients with increased S-100B compared to those with normal S-100B (p=0.02). Correlations between the pattern and intensity of S-100B expression in the tumor specimen and the value of serum the S-100B did not reach statistical significance. CONCLUSION: Serum S-100B is a valuable biomarker for the evaluation of response to treatment and prediction of early distant relapse and survival in stage IIIB/C melanoma. The marginal correlation between serum S-100B values and expression of S-100B in the tumor specimens needs further study.

Axillary recurrence after a tumour-negative sentinel node biopsy in breast cancer patients: A systematic review and meta-analysis of the literature.

BACKGROUND: Sentinel node biopsy became the standard of care before consensus on the technique was reached and without randomized studies having shown a similar or decreased axillary recurrence rate. The purpose of this study was to evaluate studies reporting on patients with a negative sentinel node biopsy. METHODS: We performed a systematic review and meta-analysis of the literature for studies concerning clinically node-negative breast cancer patients with a tumour-negative sentinel node biopsy and no subsequent axillary node dissection. The axillary recurrence rate was determined, as well as the sensitivity of the sentinel node procedure and the differences in lymphatic mapping techniques. RESULTS: Forty-eight studies concerning 14 959 sentinel node-negative breast cancer patients followed for a median of 34 months were selected. Sixty-seven patients developed an axillary recurrence, resulting in a recurrence rate of 0.3%. The sensitivity of the sentinel node biopsy was 100%. Uni- and multivariable variable analyses showed that the lowest recurrence rates were reported in studies performed in cancer centres, in studies that described the use of (99m)Tc-sulphur colloid, and also when investigators used the superficial injection technique or evaluated the harvested sentinel nodes with haematoxylin-eosin and immunohistochemistry staining (p<0.01). CONCLUSIONS: In this systematic literature review, the axillary recurrence rate in sentinel node-negative patients is 0.3%, which is well within the desired range. The median sensitivity of the procedure appears to be as high as 100%. The recurrence rate is influenced by the differences in the lymphatic mapping technique.

Excision biopsy of breast lesions changes the pattern of lymphatic drainage.

BACKGROUND: The aim was to validate the sentinel node biopsy procedure in women who had previous breast excision biopsy by means of determining the reproducibility of lymphoscintigraphy after surgery. METHODS: Twenty-five women scheduled for excision biopsy of a breast lesion were investigated. The day before surgery, (99m)Tc-labelled nanocolloid was injected into the tumour. Lymphoscintigraphy was repeated a minimum of 2 weeks after surgery. RESULTS: Preoperative lymphoscintigraphy visualized at least one sentinel node in all 25 women. Discrepancy in the drainage patterns after surgery was noted in 17 of 25 patients. A change in the drainage pattern in the axilla after excision biopsy was seen in 11 women. Drainage to the internal mammary chain was noted before surgery in 13 women, but only three had the same drainage pathways after excision biopsy. CONCLUSION: After breast excision biopsy lymphoscintigraphy usually showed a different drainage pattern. This implies that sentinel node biopsy should be performed before excision biopsy to ensure optimal sensitivity.

The health-related quality of life of long-term survivors of melanoma treated with isolated limb perfusion.

AIMS: To evaluate the generic and condition-specific health-related quality of life (HRQL) of long-term survivors of extremity melanoma treated with isolated limb perfusion (ILP). METHODS: Between 1978 and 2001, 292 patients with melanoma of the limbs underwent ILP in our institution. Of these patients, 59 were alive and disease-free for at least six months prior to study entry. Fifty-one of these 59 patients completed a mailed questionnaire assessing generic HRQL (SF-36), condition-specific HRQL (limb function, cosmetic results, fear of recurrence), and problems regarding work and insurance. An age- and gender-matched, normative sample of the Dutch general population was available for comparison of SF-36 scores. RESULTS: Mean age of patients was 57 years, 90% female, with a median time since ILP of 14 years (range 3-25 years). The SF-36 scores of the patient group were equal to or better than that of the general population, significantly for bodily pain, general health perceptions, and the physical and mental health component scores. Nevertheless, the patients reported a number of specific problems: complaints of limb function were reported by 49-55%, cosmetic problems by 31-38% and fear of local disease recurrence and distant metastases by 77 and 63% of the patients, respectively. Less than 10% of patients reported problems in obtaining a mortgage or life insurance. CONCLUSIONS: The HRQL of long-term survivors of melanoma treated with ILP appears comparable to, and sometimes better than that of healthy peers within the general population. Nevertheless, this survivor group reports a number of specific problems that impact on daily life. Although these findings need to be confirmed with larger, prospective studies, they suggest that rehabilitation should focus on improving limb functionality, and addressing chronic fear of disease recurrence.

Lymphatic mapping and sentinel node biopsy in Merkel's cell carcinoma.

AIM: The purpose of this study was to determine the predictive value of lymphatic mapping with selective lymphadenectomy in patients with Merkel's cell carcinoma. METHODS: Eight patients with biopsy proven Merkel's cell carcinoma underwent sentinel node biopsy. Lymphoscintigraphy was performed the day before surgery following intradermal injection of 74-111MBq of 99mTc-nanocolloid divided into four doses around the biopsy scar. Dynamic and static images were obtained. RESULTS: At least one sentinel node was visualized in all patients. The sentinel node was intra-operatively identified with the aid of a hand-held gamma probe in all cases and patent blue dye in six out of eight cases. During surgery, all sentinel nodes were successfully harvested. Metastatic cell deposits were subsequently identified in three patients (37.5%) and they underwent regional lymphadenectomy. No additional involved lymph nodes were identified. No recurrence has been reported in a median follow-up of 4.6 years (range: 8 months-10 years). CONCLUSIONS: In conclusion, sentinel node biopsy in patients with Merkel's cell carcinoma appears to be a reliable staging technique.

The sentinel node biopsy in patients with breast cancer; many controversies remain.

The sentinel node procedure has increasingly been used as a diagnostic tool for staging breast cancer. Although many institutes have embraced this procedure, many issues concerning the indications and the technique itself remain unsolved. In this review, several aspects regarding these controversies are discussed from the perspective of The Netherlands Cancer Institute. These include the definitions used to identify the sentinel node, the indications and contraindications for this procedure and the injection site of the tracer and blue dye. What are the clinical implications of a micro-metastasis in the sentinel node? What is the best treatment for patients with an involved axillary node? Should non-axillary sentinel nodes be pursued, and if so, what are the implications for further management of these patients? Finally, the current TNM system is discussed in perspective of the evolving sentinel node procedure. Although many questions remain to be solved, the regional recurrence rates are low when axillary clearance is omitted because of a tumor-free sentinel node.

Repeat isolated limb perfusion with TNFalpha and melphalan for recurrent limb melanoma after failure of previous perfusion.

AIM: To assess the effectiveness of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNFalpha) and melphalan for recurrent or persistent melanoma lesions after previous ILP. METHODS: Between 1978 and 2001, 21 patients (mean age 65, range 29-83 years) underwent repeat ILP for recurrent or persistent melanoma after a previous ILP. First ILPs had been performed with melphalan alone in 13 patients and with addition of TNFalpha in eight, for a median of nine lesions (interquartile (IQ) range 2-23 lesions). Repeat ILP was performed with TNFalpha and melphalan in all 21 patients for a median of nine lesions (IQ range 5-25 lesions). Median follow-up after repeat ILP was 18 months (IQ range 6-36 months). RESULTS: Thirteen patients attained a complete response (CR) after repeat ILP compared to 11 of 17 with measurable lesions after the first ILP. Nine patients relapsed after CR. Median limb recurrence-free survival was 13 months. Fourteen patients had mild acute regional toxicity after repeat ILP compared to 18 after the first ILP (n.s.). One patient underwent amputation for critical limb ischemia 10 months following repeat ILP. The limb salvage rate was 95%. Overall median survival was 62 months after CR compared to 13 months for those without CR (P=0.05). CONCLUSION: Repeat ILP with TNFalpha and melphalan is feasible after previous ILP with mild regional toxicity. The CR rate is relatively high and comparable to the first procedure with good limb recurrence-free survival and high limb salvage rate.

Palliative isolated limb perfusion for advanced limb disease in stage IV melanoma patients.

INTRODUCTION: Two to three percent of the patients with extremity melanoma develop in-transit metastases in the course of their disease. When local treatments fail, isolated limb perfusion (ILP) is a reasonable option, but is generally only applied to patients without evidence of distant metastases. We assessed the value of ILP in stage IV melanoma patients with symptomatic unresectable limb melanoma at our institutions. PATIENTS AND METHODS: A computerized database, containing all patient, tumor, ILP, and follow-up data of 505 ILPs performed in 451 patients between 1978 and 2001, allowed the selection of eight (1.8%) stage IV patients who underwent a palliative ILP for unresectable melanoma lesions on the limbs. All patients had high tumor burden limb disease, according to the combined Fraker and Rossi criteria. RESULTS: The overall tumor response rate was 88%, with 13% complete and 75% partial response rates. One patient did not respond to ILP. Three partial responding patients attained a complete remission (CR) after excision of the remaining limb lesions. The median duration of hospital stay was 12 days and acute regional toxicity was mild with slight erythema and edema in six and no signs of reaction in two patients. The median limb recurrence-free interval after CR was 6 months and the median duration from the time of distant metastases to death was 15 months. Overall ILP leads to the desired palliative effect in six patients (75%). CONCLUSION: ILP should be considered as a palliative treatment in selected stage IV melanoma patients with symptomatic advanced limb disease.

Major amputation for intractable extremity melanoma after failure of isolated limb perfusion.

AIM: The aim of this study was to analyse indications and results of amputation for intractable extremity melanoma after failure of isolated limb perfusion (ILP). METHODS: Between 1978 and 2001, 451 patients with loco-regional advanced extremity melanoma underwent 505 ILPs. Amputation of the affected extremity had to be carried out for intractable recurrent disease in 11 of these patients. RESULTS: The indications for amputation were uncontrollable pain (n=2), extensive loco-regional tumour progression (n=4), loss of ankle function due to local tumour growth (n=1), and ulcerating and fungating lesions, not responding to other treatments (n=4). Four patients developed stump recurrence after amputation. Ten patients died of melanoma metastases after a median of 11 months (range 2-110 months). Two patients survived more than 5 years after amputation. CONCLUSIONS: Major amputation is rarely indicated for intractable extremity melanoma but long-term survival can be achieved in selected patients.

High incidence of in-transit metastases after sentinel node biopsy in patients with melanoma.

BACKGROUND: The occurrence of in-transit metastases in patients with a tumour-positive sentinel node varies greatly between centres and it has been suggested that the incidence is high in this patient group. METHODS: The incidence of in-transit metastases in 61 patients who had lymph node dissection because of a tumour-positive sentinel node was compared with that in 60 patients who had palpable nodal metastases dissected. RESULTS: The incidence of in-transit metastases was 23 per cent in patients with a positive sentinel node and 8 per cent in those with palpable nodes (P = 0.027). CONCLUSION: Sentinel node biopsy was associated with a higher risk of in-transit metastases. This finding does not support the routine use of sentinel node biopsy in the management of melanoma.

Radio-guided surgery improves outcome of therapeutic excision in non-palpable invasive breast cancer.

Intratumoral injection of a radiocolloid for lymphatic mapping enables the therapeutic excision of clinically occult breast cancer with the aid of a gamma-ray detection probe. The aim of this study was to determine the success rate of radio-guided tumour excision in addition to a guide wire and to identify factors predicting clear margins. Sixty-five consecutive patients underwent radio-guided tumour excision after intratumoral injection of 99mTc-nanocolloid guided by ultrasound or stereotaxis. A localization wire was inserted after scintigraphy had been performed (group 1). The results were compared with retrospective data from 67 consecutive patients who underwent therapeutic wire-directed excision alone (group 2). Factors predicting clear margins (> or = 1 mm) were determined in a logistic regression model. Adequate margins were obtained in 83% of group 1 and in 64% of group 2 (P = 0.014). The invasive component was incompletely excised in two patients in group 1 and in 14 patients in group 2. Further surgery was performed in four patients in group 1 and in 14 patients in group 2. Factors predictive of clear margins were decreasing pathological tumour diameter (P = 0.035), increasing weight of the specimen (P = 0.046), absence of microcalcifications (P = 0.004) and absence of carcinoma in situ component (P = 0.024). Radio-guided excision was an independent predictor of complete excision of the invasive component (P = 0.012). The application of radio-guided surgery combined with wire localization seems to improve the outcome of therapeutic excision of non-palpable invasive breast cancer compared with wire-directed excision alone.

Prognostic factors for survival after isolated limb perfusion for malignant melanoma.

AIMS: Risk factors were determined for mortality within 1 year after isolated limb perfusion (ILP). METHODS: All of 439 patients who underwent ILP for melanoma of the extremities were studied. Ninety percent of the patients had MD Anderson stage IIB or III disease at the time of ILP. ILP was performed with melphalan with or without TNFalpha under mild hyperthermic (38-40 degrees C) or normothermic (37-38 degrees C) conditions in 80% of the cases. RESULTS: Sixty-nine patients died within this period, 64 of metastatic melanoma. The indication for ILP was an unresectable primary (n=3), a local recurrence (n=24) or adjuvant to excision of primary lesions (n=17) in patients with stage IIIB regional lymph node metastases. These patients or patients with stage IIIAB melanoma with satellites and/or in-transit metastases with regional lymph node metastases had a relative risk of 4.6 (95% CI 2.0-6.6) and 3.6 (95% CI 2.1-10) of dying within 1 year from ILP, respectively (p<0.001). In patients with stage IV disease (distant metastases), the relative risk was 22 (95% CI 3.8-127, p=0.001). CONCLUSION: Patients with advanced limb melanoma have an increased risk of death within 1 year after ILP when regional lymph node or distant metastases are present.

Alveolar soft-part sarcoma responding to interferon alpha-2b.

A 23-year-old woman with an alveolar soft-part sarcoma of her calf with pulmonary metastases unresponsive to chemotherapy is described. Interferon (IFN) alpha-2b induced an impressive tumour response still ongoing after IFN treatment had to be stopped because of a psychosis. An explanation of this effect is still speculative.

[Regional isolated perfusion: also applicable in elderly patients]. / Regionale isolatieperfusie: ook bij bejaarde patiënten goed toepasbaar.

In 3 patients over 75 years of age with a malignancy, limb salvage was achieved through the application of isolated limb perfusion with melphalan with or without tumour necrosis factor alpha: an 82-year-old woman with extensive locoregional melanoma metastases on her lower leg, a 78-year-old woman with a large, ulcerating recurrence of melanoma on her lower leg and an 83-year-old woman with recurrent sarcoma of the lower arm. There were no complications and the women recovered well. Isolated limb perfusion can be effectively and safely used in older patients with irresectable tumours of the extremities, offering them limb salvage for the remainder of their lives.

Eight false negative sentinel node procedures in breast cancer: what went wrong?

AIMS: The purpose of the study was to evaluate the false negative sentinel node procedures in patients with breast cancer at our institution. METHODS: A total of 606 sentinel node biopsies were performed on 599 clinical N0 breast cancer patients between January 1997 and November 2001. RESULTS: The axillary sentinel node revealed metastasis in 204 (36.1%) of the 565 patients in whom it was identified and was false negative in eight patients. Two false negative results came to light by confirmatory axillary lymph node dissection during the learning phase. Tumour-positive lymph nodes were incidentally found in the axillary tail of the simple mastectomy specimen in two patients. Excision of a firm, non-radioactive, unstained but tumour-positive non-sentinel node occurred in three other patients. One patient developed an axillary recurrence 22 months postoperatively. Presumptive causes were surgical delay, pathological sampling error and tumour blocking. CONCLUSION: Intra-operative palpation of the axilla to identify suspicious lymph nodes is recommended. In a two-day protocol, surgery should be performed first thing in the morning. Seven slices of 50-150-micro m strike an acceptable balance between sensitivity and work load for the pathologist.