A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

Appendix cancer mimicking ovarian cancer.

Appendiceal adenocarcinoma is a rare malignancy for which there is no characteristic clinical presentation. We describe five women who presented with signs and symptoms characteristic of advanced ovarian cancer but whose final diagnosis was stage IV appendiceal cancer. Between 1998 and 1999, five women treated for presumed ovarian cancer were identified as having primary appendiceal cancer. Medical records and pathology were retrospectively reviewed. The median age was 47 years (range 36-61 years). All had elevated preoperative CA125 levels with a median value of 171 micro/ml (range 46-383). Four women underwent right hemicolectomy with two requiring radical surgical tumor debulking to render them optimally debulked. Four had postoperative chemotherapy, the most common agent used was 5-flourouracil. Median survival was 6.75 months (range 19 days-11 months). Primary adenocarcinoma of the appendix is rare; therefore, the clinical utility of radical tumor debulking and chemotherapy is not well described. Given the poor survival in our series, all efforts should be considered palliative. Although this disease process is uncommon, it should be entertained by gynecologic oncologists in the differential diagnosis of an intra-abdominal mass and ascites. The ability to make the correct diagnosis and differentiate between an ovarian and appendiceal primary is critical as the treatment modalities vary.

Blue urticaria: a previously unreported adverse event associated with isosulfan blue.

The sentinel node hypothesis is predicated on the fact that a metastasis, if it exists, will have traveled on a direct path from the primary tumor through the efferent lymphatic channels to the first draining lymph node in the regional lymphatic basin, the sentinel node. Lymphatic mapping with isosulfan blue and sentinel lymphadenectomy is being increasingly used in the management of patients with melanoma, breast cancer, and other solid tumors. This trend is exposing an increasing number of patients to isosulfan blue. Although this compound is generally safe, severe reactions have been reported. We describe 2 patients who developed "blue hives" after isosulfan blue injection.

Metastasectomy for recurrent stage IV melanoma.

BACKGROUND AND OBJECTIVES: Many patients undergoing complete surgical resection of distant metastatic melanoma (American Joint Committee on Cancer [AJCC] stage IV) develop recurrent disease. We examined whether a second metastasectomy could prolong the survival of patients with recurrent stage IV melanoma. DESIGN AND PATIENTS: Retrospective review of our 8,750-patient melanoma database identified 211 patients who were rendered clinically free of disease by surgical resection of stage IV metastases during the 24-year study period (January 1971 through December 1995). Our study population comprised the 131 patients who developed recurrent stage IV disease and were followed for at least 24 months or until death. RESULTS: The median disease-free interval prior to recurrent stage IV disease was 8 months (range 0.6-91.8 months). There were 131 tumor-involved anatomic sites; the median number was one (range 1-3). Of these sites, 71 (54.2%) were soft tissue, 35 (26.7%) were pulmonary, 28 (21.4%) were gastrointestinal, 23 (17.6%) were cerebral, 13 (9.9%) were skeletal, and 2 (1.5%) were gynecologic. Median survival following treatment for recurrent stage IV melanoma was 18.2 months after complete metastasectomy, compared with 12.5 months or 5.9 months after a palliative surgical procedure or nonsurgical management, respectively. The 5-year survival rate was 20.0% (8/40) for patients in the complete surgical metastasectomy group, compared with 7.0% (3/43) and 2.1% (1/48) for those in the palliative surgical and nonsurgical groups, respectively. By multivariate analysis, the two most important prognostic factors for survival following diagnosis of recurrent stage IV melanoma were a prolonged disease-free interval to recurrence (P = 0.0001) and complete surgical metastasectomy of the recurrence (P = 0.0001). CONCLUSIONS: Metastasectomy can prolong the survival of patients with recurrent stage IV melanoma if all clinically evident tumor can be resected.

Parotid region lymphatic mapping and sentinel lymphadenectomy for cutaneous melanoma.

BACKGROUND: Routine elective superficial parotidectomy for patients with primary cutaneous melanomas of the scalp, auricle, or face has been questioned. We evaluated an alternative, i.e., lymphatic mapping and sentinel lymphadenectomy, for patients with primary cutaneous melanomas draining to the region of the parotid gland. PATIENTS: Retrospective review of our large (>8000 patients) melanoma database identified 39 patients with primary melanomas (American Joint Committee on Cancer stage I or II) of the scalp (n = 19), auricle (n = 11), or face (n = 9) who underwent intraoperative lymphatic mapping to identify a sentinel node (SN) in the region of the parotid gland, between June 1985 and July 1997. RESULTS: A SN was identified in the parotid region of 37 patients (94.9%), four of whom had SN metastases. The mean number of SN obtained was 2.3/patient (range, 1-4/patient). The two patients (5.1%) for whom a parotid-region SN could not be identified underwent superficial parotidectomy during the same operation. Among the 33 patients with tumor-free SN, with a median follow-up period of 33.2 months (range, 1-121 months), there was one (3.1%) intraparotid recurrence; thus, the false-negative rate was 3.1%. The procedure-related surgical morbidity rate was only 2.6% (one case of temporary facial nerve paresis). CONCLUSIONS: For patients with primary melanomas of the scalp, auricle, or face, sentinel lymphadenectomy can be performed accurately in the parotid region and offers a low-morbidity alternative to routine elective superficial parotidectomy.

Optimal histopathologic examination of the sentinel lymph node for breast carcinoma staging.

Sentinel lymph node dissection is a minimally invasive surgical technique for staging of breast carcinoma. The optimal pathologic examination of the sentinel node (SN) has not yet been determined. Our standard protocol for evaluation of the SN in patients with breast cancer included frozen section at one level, plus paraffin sections at two levels, separated by 40 microm, and stained with hematoxylin and eosin and cytokeratin immunohistochemistry (IHC) at each paraffin section level. In the current study, we evaluated the use of step sections and cytokeratin IHC in 60 SNs (42 consecutive patients) that were tumor-negative on frozen section and hematoxylin and eosin staining at permanent section levels 1 and 2. The SN were reexamined with cytokeratin IHC at eight additional levels (levels 3-10) of the paraffin block, each separated by 40 microm. Previous IHC sections from levels 1 and 2 had shown micrometastases in nine SNs (eight patients) and no tumor cells in the remaining 51 SNs (34 patients). Of the 51 previously negative SNs, only two (4%) SNs from one (3%) patient had metastatic carcinoma cells in levels 3-10. Thus, the additional step sections with cytokeratin IHC did not significantly increase the number of patients with tumor-positive SNs. We currently recommend that the SN be examined with cytokeratin IHC at two levels of the paraffin block. This should optimize sentinel lymph node dissection as a staging technique and minimize the labor and financial burden associated with multiple step sections and IHC stains.

The role of intraoperative lymphatic mapping and sentinel lymphadenectomy in the management of patients with breast cancer.

Sentinel lymph node dissection is a highly accurate method of axillary staging in patients with early breast cancer. Focused histopathologic evaluation of the SN improves axillary staging by increasing the detection of micrometastases, but the clinical significance of micrometastatic axillary involvement remains unclear. Sentinel lymph node dissection, which can be performed on an outpatient basis with local anesthesia, appears to have less morbidity and fewer complications and be more cost effective than routine ALND. Refinement of the technical aspects of the procedure has allowed identification of the SN in over 90% of patients, with 100% diagnostic accuracy in our most recent series. We have therefore abandoned routine ALND in selected patients with invasive breast cancer and reserve this procedure only for those with tumor-involved SNs or those in whom the SN cannot be identified. Several issues such as the definition of a hot SN, the kinetics of various radioisotopes used for breast lymphoscintigraphy, and the problem of radioactive scatter must be resolved. Because no other method accurately predicts axillary node status without complete ALND, SLND merits evaluation in a prospective, randomized multicenter trial to determine whether it may become the standard method of axillary staging.

Cytoreductive surgery and adjuvant immunotherapy: a new management paradigm for metastatic melanoma.

Although patients with metastatic disease are usually not offered surgery as part of their comprehensive treatment plan, the authors suggest that surgical reduction of the tumor burden may enhance the host immune response and create a favorable setting for the use of active specific immunotherapy.

Therapeutic effect of sentinel lymphadenectomy in T1 breast cancer.

OBJECTIVE: To evaluate whether the tumor status of the sentinel lymph node (SN) would alter the systemic adjuvant therapy administered to patients with T1 breast cancer. DESIGN AND PATIENTS: Consecutive breast cancer patients (tumors < or = 2 cm) who underwent successful sentinel lymphadenectomy. MAIN OUTCOME MEASURES: Metastatic tumor in the SN, primary tumor size, recommendations for systemic adjuvant therapy before and after histopathologic evaluation of the SN, and actual systemic adjuvant therapy received by the patient. RESULTS: Of 142 total patients, 14 had T1a tumors; 35, T1b; and 93, T1c. Recommendations for systemic adjuvant therapy were initially determined solely by primary tumor characteristics and menopausal status. These recommendations were compared with recommendations for systemic adjuvant therapy based on tumor characteristics, menopausal status, and SN status; and then were compared with actual systemic adjuvant therapy received by the patient. Among the 118 patients with T1a, T1b, and favorable (positive estrogen or progesterone receptors and a low S-phase percentage with respect to DNA content) T1c tumors, 15 (37.5%) of 40 premenopausal patients and 20 (25.6%) of 78 postmenopausal patients became candidates for chemotherapy when examination of the SN revealed axillary metastasis; chemotherapy was actually administered to all 15 premenopausal patients but to only 6 postmenopausal patients. In the remaining 24 patients with unfavorable T1c tumors, SN status did not change the recommendation for chemotherapy but may have altered the choice of specific chemotherapeutic agents. CONCLUSIONS: Identification of tumor-involved SN may alter systemic adjuvant therapy in patients with T1a, T1b, and favorable T1c tumors and may potentially change the type or dose of chemotherapeutic agents given to patients with unfavorable T1c tumors. Surgical axillary staging of the axilla remains an essential part of breast cancer management and should not be abandoned.

Lymphatic mapping and sentinel lymphadenectomy for melanoma.

Intraoperative lymphatic mapping and sentinel lymphadenectomy (SLND) for patients with clinical Stage I melanoma was developed to determine the tumor status of the regional lymphatic basin without elective regional node dissection. Only individuals with histologically confirmed sentinel node (SN) metastases undergo complete regional node dissection, sparing those with tumor-free SN the morbidity of this procedure. Studies worldwide have confirmed the validity of the SN concept and the accuracy of SLND as a staging procedure. The incidence of false-negative SN and the rate of recurrence in the regional node basin have been low. Routine preoperative lymphoscintigraphy and refinements in surgical technique have improved the accuracy of SLND for melanoma, making it the nodal staging procedure of choice when undertaken by an experienced nuclear medicine physician, surgical oncologist and pathologist. Ongoing studies are investigating the impact of SLND on survival as well as the prognostic significance of micrometastasis detected by histopathologic and molecular techniques.

Overview of melanoma vaccines: active specific immunotherapy for melanoma patients.

Although a phase III trial has yet to show a statistically significant improvement in the disease-free or overall survival of melanoma patients receiving vaccine therapy, several phase II trials have shown enhanced disease-free and overall survival of patients who develop a humoral and/or cellular response to a melanoma vaccine. The challenge of active specific immunotherapy research is to determine which combination of humoral and cellular immune responses optimizes clinical outcome and how to monitor the immune response effectively. This review identifies key components of a successful melanoma vaccine, discusses new ways to modulate and stimulate the immune system, and summarizes some of the important clinical trials of active specific immunotherapy for patients with melanoma.

Surgical resection as the treatment of choice for melanoma metastatic to the lung.

Available data suggest that patients who have a limited number of pulmonary metastases may benefit from complete surgical resection if they have favorable prognostic features such as a long TDT and a long DFI. If a patient is not a surgical candidate because of radiographic evidence of extrapulmonary disease, a short TDT, or a short DFI, then concurrent or sequential biochemotherapy offers the best chance for a complete response and remission.

Tumor doubling time: a selection factor for pulmonary resection of metastatic melanoma.

BACKGROUND AND OBJECTIVES: Melanoma patients have a 20-27% rate of 5-year survival after surgical resection of pulmonary metastases. We evaluated tumor doubling time (TDT) and other prognostic factors in an attempt to identify candidates for pulmonary metastasectomy. METHODS: Review of our large melanoma database identified 129 patients who underwent complete or partial resection of pulmonary metastases. At least two preoperative chest roentgenograms were available for 45 patients; these images were used by a single examiner to measure tumor width and length. The mean of the diameters was plotted against time on semilogarithmic paper: the slope of the line approximated tumor growth rate, and TDT was proportional to the inverse of the tumor growth rate. RESULTS: For the 45 patients with a calculated TDT, median survival was 23.1 months and 5-year survival rate was 15.6% (7/45). By multivariate analysis, the only prognostically significant factors were TDT (P=0.006) and type of pulmonary resection (P=0.022). When TDT was <60 days, median survival was 16.0 months, and 5-year survival rate was zero; when TDT was > or = 60 days, median survival was 29.2 months (log-rank test; significant at P < 0.0001) and 5-year survival rate was 20.7% (6/29) (P < 0.0001). CONCLUSIONS: TDT is the most significant preoperative prognostic factor for patients undergoing pulmonary resection of metastatic melanoma. If TDT is <60 days, a preoperative neoadjuvant regimen of chemotherapy and biologic therapy is recommended. Pulmonary metastasectomy should not be attempted if TDT cannot be increased to > or = 60 days by systemic therapy.

Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma.

BACKGROUND AND OBJECTIVE: The sentinel node hypothesis assumes that a primary tumor drains to a specific lymph node in the regional lymphatic basin. To determine whether the sentinel node is indeed the node most likely to harbor an axillary metastasis from breast carcinoma, the authors used cytokeratin immunohistochemical staining (IHC) to examine both sentinel and nonsentinel lymph nodes. METHODS: From February 1994 through October 1995, patients with breast cancer were staged with sentinel lymphadenectomy followed by completion level I and II axillary dissection. If the sentinel node was free of metastasis by hematoxylin and eosin staining (H&E), then sentinel and nonsentinel nodes were examined with IHC. RESULTS: The 103 patients had a median age of 55 years and a median tumor size of 1.8 cm (58.3% T1, 39.8% T2, and 1.9% T3). A mean of 2 sentinel (range, 1-8) and 18.9 nonsentinel (range, 7-37) nodes were excised per patient. The H&E identified 33 patients (32%) with a sentinel lymph node metastasis and 70 patients (68%) with tumor-free sentinel nodes. Applying IHC to the 157 tumor-free sentinel nodes in these 70 patients showed an additional 10 tumor-involved nodes, each in a different patient. Thus, 10 (14.3%) of 70 patients who were tumor-free by H&E actually were sentinel node-positive, and the IHC lymph node conversion rate from sentinel node-negative to sentinel node-positive was 6.4% (10/157). Overall, sentinel node metastases were detected in 43 (41.8%) of 103 patients. In the 60 patients whose sentinel nodes were metastasis-free by H&E and IHC, 1087 nonsentinel nodes were examined at 2 levels by IHC and only 1 additional tumor-positive lymph node was identified. Therefore, one H&E sentinel node-negative patient (1.7%) was actually node-positive (p < 0.0001), and the nonsentinel IHC lymph node conversion rate was 0.09% (1/1087; p < 0.0001). CONCLUSIONS: If the sentinel node is tumor-free by both H&E and IHC, then the probability of nonsentinel node involvement is <0.1%. The true false-negative rate of this technique using multiple sections and IHC to examine all nonsentinel nodes for metastasis is 0.97% (1/103) in the authors' hands. The sentinel lymph node is indeed the most likely axillary node to harbor metastatic breast carcinoma.

Update on active specific immunotherapy with melanoma vaccines.

Although a randomized clinical trial has yet to show a statistically significant improvement in the survival of patients receiving vaccine therapy for malignant melanoma, several studies have shown enhanced survival of patients developing an immune response to a melanoma vaccine. The knowledge and techniques of modern molecular biology and immunology suggest multiple strategies to augment this response. The challenge of immunotherapy research is to determine which combination of approaches leads to a favorable clinical response and how to monitor that response effectively. This review identifies components of a successful vaccine, discusses new ways to modulate and stimulate the immune system, and summarizes some of the more interesting clinical trials of melanoma vaccine immunotherapy.