Constantine P. Karakousis

Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger

OBJECTIVE A prospective multi-institutional randomized surgical trial involving 740 stage I and II melanoma patients was conducted by the Intergroup Melanoma Surgical Program to determine whether elective (immediate) lymph node dissection (ELND) for intermediate-thickness melanoma (1-4 mm) improves survival rates compared with clinical observation of the lymph nodes. A second objective was to define subgroups of melanoma patients who would have a higher survival with ELND. METHODS The eligible patients were stratified according to tumor thickness, anatomic site, and ulceration, and then were prerandomized to either ELND or nodal observation. Femoral, axillary, or modified neck dissections were performed using standardized surgical guidelines. RESULTS The median follow-up was 7.4 years. A multifactorial (Cox regression) analysis showed that the following factors independently influenced survival: tumor ulceration, trunk site, tumor thickness, and patient age. Surgical treatment results were first compared based on randomized intent. Overall 5-year survival was not significantly different for patients who received ELND or nodal observation. However, the 552 patients 60 years of age or younger (75% of total group) with ELND has a significantly better 5-year survival. Among these patients, 5-year survival was better with ELND versus nodal observation for the 335 patients with tumors 1 to 2 mm thick, the 403 patients without tumor ulceration, and the 284 patients with tumors 1 to 2 mm thick and no ulceration. In contrast, patients older than 60 years of age who had ELND actually had a lower survival trend than those who had nodal observation. When survival rates were compared based on treatment actually received (i.e., including crossover patients), the patients with significantly improved 5-year survival rates after ELND included those with tumors 1 to 2 mm thick, those without tumor ulceration, and those 60 years of age or younger with tumors 1 to 2 mm thick or without ulceration. CONCLUSION This is the first randomized study to prove the value of surgical treatment for clinically occult regional metastases. Patients 60 years or age or younger with intermediate-thickness melanomas, especially with nonulcerative melanoma and those with tumors 1 to 2 mm thick, may benefit from ELND. However, because some patients still are developing distant disease, these results should be considered an interim analysis.

Sentinel node biopsy for early-stage melanoma - Accuracy and morbidity in MSLT-I, an international multicenter trial

Objective:The objective of this study was to evaluate, in an international multicenter phase III trial, the accuracy, use, and morbidity of intraoperative lymphatic mapping and sentinel node biopsy (LM/SNB) for staging the regional nodal basin of patients with early-stage melanoma. Summary Background Data:Since our introduction of LM/SNB in 1990, this technique has been widely adopted and has become part of the American Joint Committee on Cancer (AJCC) staging system. Eleven years ago, the authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT-I) to compare 2 treatment approaches: wide excision (WE) plus LM/SNB with immediate complete lymphadenectomy (CLND) for sentinel node (SN) metastases, and WE plus postoperative observation with CLND delayed until the subsequent development of clinically evident nodal metastases. Methods:After each center achieved 85% accuracy of SN identification during a 30-case learning phase, patients with primary cutaneous melanoma (≥1 mm with Clark level ≥III, or any thickness with Clark level ≥IV) were randomly assigned in a 4:6 ratio to WE plus observation (WEO) with delayed CLND for nodal recurrence, or to WE plus LM/SNB with immediate CLND for SN metastasis. The accuracy of LM/SNB was determined by comparing the rates of SN identification and the incidence of SN metastases in the LM/SNB group versus the subsequent development of nodal metastases in the regional nodal basin of those patients with tumor-negative SNs. Early morbidity of LM/SNB was evaluated by comparing complication rates between the 2 treatment groups. Trial accrual was completed on March 31, 2002, after enrollment of 2001 patients. Results:Initial SN identification rate was 95.3% overall: 99.3% for the groin, 95.3% for the axilla, and 84.5% for the neck basins. The rate of false-negative LM/SNB during the trial phase, as measured by nodal recurrence in a tumor-negative dissected SN basin, decreased with increasing case volume at each center: 10.3% for the first 25 cases versus 5.2% after 25 cases. There were no operative mortalities. The low (10.1%) complication rate after LM/SNB increased to 37.2% with the addition of CLND; CLND also increased the severity of complications. Conclusions:LM/SNB is a safe, low-morbidity procedure for staging the regional nodal basin in early melanoma. Even after a 30-case learning phase and 25 additional LM/SNB cases, the accuracy of LM/SNB continues to increase with a centers experience. LM/SNB should become standard care for staging the regional lymph nodes of patients with primary cutaneous melanoma.

Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial.

BACKGROUND A prospective, multi-institutional, randomized surgical trial involving 486 localized melanoma patients was conducted to determine whether excision margins for intermediate-thickness melanomas (1.0 to 4.0 mm) could be safely reduced from the standard 4-cm radius. METHODS Patients with 1- to 4-mm-thick melanomas on the trunk or proximal extremities were randomly assigned to receive either a 2- or 4-cm surgical margin. RESULTS The median follow-up time was 6 years. The local recurrence rate was 0.8% for 2-cm margins and 1.7% for 4-cm margins (p value not significant [NS]). The rates of in-transit metastases were 2.1% and 2.5%, respectively (p = NS). Of the six patients with local recurrences, five have died. Recurrence rates did not correlate with surgical margins, even among stratified thickness groups. The overall 5-year survival rate was 79.5% for the 2-cm margin patients and 83.7% for the 4-cm margin patients (p = NS). The need for skin grafting was reduced from 46% with 4-cm surgical margins to 11% with 2-cm surgical margins (p < 0.001). The hospital stay was shortened from 7.0 days for patients receiving 4-cm surgical margins to 5.2 days for those receiving 2-cm margins (p = 0.0001). This reduction was largely due to reduced need for skin grafting, since the hospital stay for those who had a skin graft was 2.5 days longer than that for those who had a primary wound closure (p < 0.01). CONCLUSION Margins of excision can be safely reduced to 2 cm for patients with intermediate-thickness melanomas. The narrower margins significantly reduced the need for skin grafting and shortened the hospital stay.

Cytogenetic studies of adipose tissue tumors. II. Recurrent reciprocal translocation t(12;16)(q13;p11) in myxoid liposarcomas

Detailed chromosome studies, briefly reported previously, from short-term cultures of tumor cells from myxoid liposarcomas are reported. A common reciprocal translocation, t(12;16)(q13;p11), was found in three cases and a complex t(1;12;16)(p11;q13;p11) in the fourth one. This nonrandom primary change, not described before in solid tumors, could characterize the myxoid form of liposarcoma. The involvement of a closely located breakpoint on chromosome #12 in a reciprocal t(3;12)(q28;q14) described in a lipoma in the previous article of this series, suggests a common basis in the biological process of proliferation of tumors sharing a common histogenesis.

Feasibility of limb salvage and survival in soft tissue sarcomas

One hundred nine consecutive patients with soft tissue sarcomas were treated in the period 1977 through 1983. Of 85 patients with extremity sarcomas, only 3 patients (4%) were managed with amputation, whereas in the previous decade, 40% of such patients were treated with amputation in our institute. The current 5‐year survival rate is 63%; in the previous decade it was 45%. In the current series, for extremity locations, patients with minimum surgical margins of 2 cm or greater and no further local therapy had a 5‐year local recurrence rate of 17%, whereas those with minimum surgical margins of less than 2 cm and who were treated with adjuvant postoperative radiation had a local recurrence rate of 7%. In the previous period, the local recurrence rate was 30% after wide resection and 66.6% after local excision. With a combination of modalities, limb salvage can be practiced currently in the majority of patients with extremity soft tissue sarcomas without any adverse effect on recurrence rates and survival.

Cytogenetic studies of adipose tissue tumors. I. A benign lipoma with reciprocal translocation t(3;12)(q28;q14).

Detailed clinical histories and cytogenetic investigations using short-term cultures are reported in three typical benign lipomas. Although a diploid (normal) karyotype was observed in two cases, a reciprocal chromosome translocation t(3;12)(q28;q14) was found in the third case, which was briefly reported previously. These data are discussed in light of a lipoma with similar karyotypic changes reported by Heim et al. and a similar translocation observed by us in malignant myxoid liposarcomas. The nonrandom involvement of segment 12q13-q14 in benign and malignant lipomatous tumors suggest a common basis for at least one of the possible multiple steps in the genesis of neoplastic processes.

Malignant melanoma brain metastases. Review of roswell park memorial institute experience

One‐hundred twenty five of 700 patients with malignant melanoma treated at Roswell Park Memorial Institute from 1972 to 1978 were found to have brain metastases. Seventy‐three percent of the patients had multiple brain metastases. Male to female ratio was 1.9:1. The median survival of the untreated group of patients was 3 weeks as compared with that of 6 weeks for the patients maintained on steroids only, 9 weeks for those who received radiotherapy, 11 weeks for the patients treated with intraarterial chemotherapy, and 26 weeks for the patients who underwent successful surgical excision of a solitary lesion.

Desmoid tumors and their management

Nineteen cases of desmoid tumors were reviewed, being intraabdominal. Five of the 7 were associated with polyposis coli. The remaining 12 cases were distributed in different anatomic locations. Sixteen patients were treated with resection either alone or in combination with radiation or hormonal treatment. There were two deaths due to unrelated causes, and the rest of the patients (89 percent) are alive. At present, 16 of the surviving 17 patients are disease-free with a mean follow-up of 6 years. In two of eight patients who were initially treated with wide excision at our center, local recurrence developed, and five patients treated with resection elsewhere were referred because of recurrence. Six patients treated with simple resection and adjuvant radiation remain free of disease with a mean follow-up of 5 1/2 years.

Prognostic parameters in recurrent malignant melanoma

In 361 patients with recurrent malignant melanoma, the clinical stage was the strongest determinant of subsequent survival (P < 0.01). In Stage IV, the number of initial, distinct lesions was important. Patients presenting with a single metastatic nodule had median survival ten months, whereas those with two or more metastatic nodules had median survival 6.9 months (P < 0.05). The length of disease‐free interval from excision of the primary to recurrence correlated consistently with subsequent survival in patients with regional lymph node metastases. Those with disease‐free interval less than one year had median survival 15.8 months with 16% surviving at five years, while those with interval one year or longer had median survival 23.7 months with 30% surviving at five years (P < 0.05). In Stage IV, the correlation of survival with disease‐free interval became significant only with 24 months as the demarcation point of length of disease‐free interval. Age and sex affected the disease‐free interval, but not survival after recurrence.

Gastrointestinal metastases from malignant melanoma

Between 1980 and 1992, 68 patients with clinical indications of involvement of the gastrointestinal (GI) tract with metastatic melanoma were treated at Roswell Park Cancer Institute. Presenting symptoms were anaemia, abdominal pain, nausea and vomiting. Sites commonly involved were the small bowel (75%), the large intestine (25%), and the stomach (16%). Twenty-one patients were considered unsuitable for surgery; their median survival after diagnosis of GI metastases was 2.9 months. Forty-seven patients underwent abdominal surgery; effective palliation was achieved in most of them. Complete resection of GI metastases was accomplished in 47% of patients. The median survival after operation was 27.6 months for patients with complete resection of GI metastasis and no other disease, 5.1 months for patients with resection of involved GI tract and other metastases present, and 1.9 months for patients who had a by-pass procedure only. The 5-year survival for patients with complete resection of GI metastases and no other evidence of disease was 28.3%. The other groups had only 1-year survivors. Surgical intervention is justified on the basis of these findings, and extended palliation can be achieved in patients with complete resection of metastatic disease.