Thromboembolic Events Associated with Thalidomide and Multimodality Therapy for Soft Tissue Sarcomas: Results of RTOG 0330.

Introduction. RTOG 0330 was developed to address the toxicity of RTOG 9514 and to add thalidomide (THAL) to MAID chemoradiation for intermediate/high grade soft tissue sarcomas (STSs) and to preoperative radiation (XRT) for low-grade STS. Methods. Primary/locally recurrent extremity/trunk STS: ≥8 cm, intermediate/high grade (cohort A): >5 cm, low grade (cohort B). Cohort A: 3 cycles of neoadjuvant MAID, 2 cycles of interdigitated THAL (200 mg/day)/concurrent 22 Gy XRT, resection, 12 months of adjuvant THAL. Cohort B: neoadjuvant THAL/concurrent 50 Gy XRT, resection, 6 months of adjuvant THAL. Planned accrual 44 patients. Results. 22 primary STS patients (cohort A/B 15/7). Cohort A/B: median age of 49/47 years; median tumor size 12.8/10 cm. 100% preoperative THAL/XRT and surgical resection. Three cycles of MAID were delivered in 93% cohort A. Positive margins: 27% cohort A/29% cohort B. Adjuvant THAL: 60% cohort A/57% cohort B. Grade 3/4 venous thromboembolic (VTE) events: 40% cohort A (1 catheter thrombus and 5 DVT or PE) versus 0% cohort B. RTOG 0330 closed early due to cohort A VTE risk and cohort B poor accrual. Conclusion. Neoadjuvant MAID with THAL/XRT was associated with increased VTE events not seen with THAL/XRT alone or in RTOG 9514 with neoadjuvant MAID/XRT.

Factors associated with actual long-term survival following soft tissue sarcoma pulmonary metastasectomy.

AIMS: To identify clinicopathologic and treatment variables associated with long-term overall survival (OS) in soft tissue sarcoma (STS) patients with lung metastases undergoing pulmonary metastasectomy (PM). METHODS: Retrospective review of 94 STS PM patients with an actual follow-up > or = 5 years. Data were collected on demographics, tumor features, treatment, and outcome. RESULTS: Most primary tumors were intermediate/high grade and the common histopathologies were evenly distributed. Half of the primary tumors were located on the extremities. The mean disease-free interval (DFI) from time of original diagnosis until metastases was 25 months (median 15 months). Eighteen patients had synchronous metastatic disease. Bilateral pulmonary metastases and >1 metastasis were common. The median number of metastases resected was 2.5. Thirty-four patients had extrapulmonary tumor at the time of PM; all extrapulmonary disease was resected. Negative margin resection (R0) PM was performed in 74 patients. Actual 5-year disease-free survival (DFS) and OS for all patients were 5% and 15%, respectively. For the R0 group, actual 5-year DFS and OS were 7% and 18%, respectively. R0 resection and a prolonged DFI were associated with improved OS. Patient characteristics, tumor features, local recurrence, and adjuvant therapy did not affect OS. CONCLUSIONS: Less than 20% of STS PM patients will survive 5 years. Complete resection and DFI are the most predictive factors for prolonged survival.

The anti-tumor effect of interleukin-12 is enhanced by mild (fever-range) thermal therapy.

The cytokine interleukin 12 (IL-12) has resulted in notable anti-tumor activity in animal models and in patients and as a result there is considerable interest in learning how to maximize its therapeutic potential while at the same time reducing its known toxic side effects. Strategies which could maintain its effectiveness while permitting reduced dosage could be especially valuable. In this study we used BALB/c mice bearing CT26 tumors as a model for testing whether combining murine IL-12 with a mild (fever range) whole body hyperthermia protocol could result in such a strategy. Our data revealed that 100 ng of IL-12/mouse/day used in combination with FR-WBH was as effective as one in which 300 ng of IL-12/mouse/day was used alone. Importantly, the mice receiving the combination treatment exhibited fewer treatment related toxicities compared to those that received high dose IL-12 alone. Initiation of the IL-12 treatment immediately after FR-WBH induced the greatest anti-tumor effect. This effect does not appear to depend on differences in IL-12-induced IFN-gamma, but may involve production of nitric oxide (NO), since treatment of mice with a NOS inhibitor, NG-monomethyl-L-arginine (L-NMA), abolishes the additive anti-tumor effect of the combination treatment. Collectively, these data suggest that modification of physiological parameters in the host by mild fever-like thermal stimuli may be an effective and feasible adjuvant for cytokine-based immunotherapeutic strategies.

A phase I study of fever-range whole body hyperthermia (FR-WBH) in patients with advanced solid tumours: correlation with mouse models.

Various studies in animal tumour models have revealed the potential of fever-range whole body hyperthermia (FR-WBH) to be used in cancer therapy. To determine the safety of FR-WBH treatment in the clinic, patients with advanced solid tumours were heated in the outpatient setting to 39-39.5 degrees C for 3 or 6h, or 39.5-40 degrees C for 6h using the Heckel-HT 2000 apparatus. These WBH treatments were well tolerated, with no significant adverse events related to cardiac, hepatic, renal or pulmonary systems. In the majority of patients, flow cytometric analysis of peripheral blood leukocyte populations indicated that there were transient decreases in the number of circulating T lymphocytes and a concomitant decrease in the number of L-selectin positive lymphocytes in the peripheral blood. These findings closely mimic the affects seen previously in pre-clinical murine studies in which this same fever-like treatment was shown to inhibit tumour growth. These studies have established the safety of this treatment and will allow for future clinical trials where application of FR-WBH treatment can be combined with other anti-cancer therapies, including immunotherapy and chemotherapy.

Local excision of rectal carcinoma.

The purpose of this study was to identify the recurrence rate, the salvage rate after recurrence, and the overall survival after local excision of rectal adenocarcinomas. A retrospective medical chart review was performed in 31 consecutive patients with rectal adenocarcinoma who underwent local excision at Roswell Park Cancer Institute from January 1990 through December 1999. After excision nine patients were excluded from further analysis because they were found to have advanced stage on pathologic examination (T2 primary tumors with vascular invasion or T3 tumors). Eight of the nine patients underwent abdominoperineal resection as definitive therapy. In the remaining 22 patients who underwent transanal excision as definitive surgical therapy there were 13 patients with T1 tumors and nine patients with T2 tumors. Overall seven patients (32%) developed local recurrences after local excision. This included four patients with T1 and three patients with T2 primary tumors. All recurrences occurred in the seven patients who did not receive adjuvant chemoradiation. All patients underwent salvage resection of the recurrence. Four patients who underwent salvage resection of the recurrence remain without evidence of disease at a median follow-up of 19.5 months. Local excision without adjuvant therapy has an unacceptably high rate of local recurrence. Although most patients who recur locally are salvaged by radical resection the long-term results after resection remain unknown. The use of adjuvant chemoradiation appears to reduce this high recurrence rate and may eventually become a standard adjunct to local excision of rectal cancer.

Clear cell sarcoma: the Roswell Park experience.

BACKGROUND AND OBJECTIVES: Clear cell sarcoma of the tendons and aponeuroses (CCSTA) is an aggressive, rare soft-tissue tumor with approximately 300 reported cases. Although it appears to be histogenetically related to melanoma, its clinical behavior resembles soft tissue sarcoma with a propensity for lymph node metastases. We report our experience at a tertiary cancer center. METHODS: Eight cases of CCSTA evaluated at Roswell Park Cancer Institute between 1970 and 1998 were reviewed retrospectively. Patient data analyzed included patient age, gender, anatomic location, size of tumor, development of local, regional and distant recurrence, and patient status at last follow up. RESULTS: Six of eight patients were alive at 2 years, while three of seven patients were alive at 5 years. Of the patients alive with no evidence of recurrence, two had tumors of less than 2 cm, and the remaining patient had incomplete information regarding tumor size. Five patients recurred within 2 years of definitive surgical management. Four had tumors > 5 cm. All five patients progressed to metastatic disease at a median follow up of 20 months (range 1-108 months) following definitive surgical management and all eventually died of their disease at a median of 3 months (range 0-24 months) from presentation with metastatic disease. Four of five patients with lesions > 5 cm received adjuvant chemotherapy with intent to cure, but all eventually died of disease at 4, 22, 34, and 41 months from initial presentation. CONCLUSIONS: CCSTA is an aggressive tumor of the soft tissues. Early recognition and management are associated with an excellent long-term prognosis. Tumors greater than 5 cm warrant aggressive surgical management and treatment, and are at high risk of the development of distant disease. Aggressive multiagent chemotherapy appeared to have no impact on outcome. Other adjuvant therapeutic options including immunotherapy should be investigated.

Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade.

INTRODUCTION: Vascular endothelial growth factor (VEGF), an endothelial-specific mitogen overexpressed in various epithelial malignancies is thought to be a potent regulator of angiogenesis. We hypothesized that some soft tissue sarcomas, due to their high propensity for hematogenous metastases (1) would overexpress VEGF, (2) that the degree of expression may represent a significant biologic predictor for disease-specific survival, and (3) that recurrent tumor would express as high or higher VEGF compared with the primary tumor. METHODS: Selected paraffin-embedded tissue of surgical specimens from 79 patients with soft tissue sarcomas, treated between 1989 and 1995 were stained with a rabbit polyclonal anti-VEGF antibody at a concentration of 2 microg/ml. Slides were assessed for VEGF expression as high or low by two investigators blinded to the clinicopathologic data. Twelve patients had VEGF expression of their primary tumors, and their recurrent tumors were compared. The Fishers' exact test assessed for differences in VEGF expression; survival analyses were performed according to the methods of Kaplan and Meier. RESULTS: Seventy-eight percent (29 of 37) of patients who died of disease had high VEGF expression. However, VEGF expression was not an independent predictor of either overall or disease-free survival. Tumor grade correlated with VEGF expression significantly. For the low-grade tumors, 7 of 13 expressed low VEGF, whereas for high-grade tumors, 53 of 66 expressed high VEGF (P = .016). Seven of the 12 paired tumor samples expressed identical VEGF immunostaining. CONCLUSIONS: The majority of high-grade soft tissue sarcomas in this study have high intensity VEGF expression. This finding may provide useful information on individual soft tissue sarcomas and offer the basis for therapeutic and biologic targeting in high-risk patients using anti-angiogenesis strategies. However, in our analysis, after accounting for tumor grade, VEGF does not seem to be an independent predictor of clinical outcome.

Malignant fibrous histiocytoma: an institutional review.

BACKGROUND: A thorough understanding of malignant fibrous histiocytoma (MFH), the most common subtype of soft tissue sarcoma, will lead to improved histologic-specific protocols. METHODS: 126 patients with histologically confirmed MFH were analyzed. The median follow-up was 42 months (range 1-233 months). RESULTS: Overall survival was 58% at 5 years and 38% at 10 years. Grade significantly influenced prognosis, with 10-year survival of 90%, 60%, and 20% for low, intermediate, and high grade tumors, respectively (p = 0.0007). Distant metastases at initial presentation (p = 0.0002) and size of the primary tumor (p = 0.0007) influenced outcome. Neither anatomic site nor depth of the primary tumor were significant prognostic factors. Positive microscopic margins were associated with a decreased disease-free survival (p = 0.006). CONCLUSIONS: Tumor grade, size, and distant metastases at initial presentation remain the most important prognostic factors for MFH. Resection with negative microscopic margins decreased the incidence of local recurrence.

Risk factors for nodal recurrence after lymphadenectomy for melanoma.

BACKGROUND: The risk and outcome of regional failure after elective and therapeutic lymph node dissection (ELND/TLND) for microscopically and macroscopically involved lymph nodes without adjuvant radiotherapy were evaluated. METHODS: Retrospective melanoma database review of 338 patients (ELND 85, TLND 253) from 1970 to 1996 with pathologically involved lymph nodes. RESULTS: Regional recurrence occurred in 14% of patients treated with ELND (n = 12) and 28% of patients treated with TLND (n = 72; P = .009). Risk factors associated with nodal recurrence were advanced age, primary lesion in the head and neck region, depth of the primary lesion, number of involved lymph nodes, and extracapsular extension (ECE). For each nodal basin, the ELND group had a lower incidence of recurrence than the TLND group. The TLND group had larger lymph nodes, greater number of involved lymph nodes, and a higher incidence of ECE. The 10-year disease-specific survival was 51% vs. 30% for ELND and TLND, respectively (P = .0005). Nodal basin failure was predictive of distant metastasis, with 87% developing distant disease compared with 54% of patients without nodal recurrence (P < .0001). Of six patients who underwent a second dissection after isolated nodal recurrence, five patients have had a median disease-free interval of 79 months. CONCLUSIONS: After ELND or TLND, patients who have a large tumor burden (thick primary melanoma, multiply involved lymph nodes, ECE), advanced age, and a primary lesion located in the head and neck have a significantly increased likelihood of relapse and a decreased survival. Few patients present with an isolated nodal recurrence, but the majority can be salvaged by a second dissection.

Alveolar soft part sarcoma metastatic to small bowel mucosa causing polyposis and intussuseption.

A report of alveolar soft part sarcoma metastatic to the small bowel is presented. Hematogenous metastases to the small bowel from primary tumors outside the abdominal cavity are uncommon, and most remain asymptomatic and are not discovered until autopsy. However, small bowel metastases can lead to intestinal obstruction, intussuseption or even perforation. While metastases to the small bowel have been described for other tumor types, including melanoma and lung cancer, this is extremely uncommon for sarcoma, especially alveolar soft part sarcoma. We describe a 42-year-old male with a long history of alveolar soft part sarcoma, metastatic to the lung and brain, who developed an intussuseption from metastases to the small bowel.

Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management.

Gastrointestinal stromal tumors (GIST) are rare tumors of the gastrointestinal (GI) tract that arise from primitive mesenchymal cells. GISTs occur throughout the GI tract but are usually located in the stomach and small intestine. The majority of GISTs are immunohistochemically positive for c-kit protein (CD 117) and CD34. GISTs express a heterogeneous clinical course not easily predicted by standard pathological means. The most important prognostic factors are size > 5 cm, tumor necrosis, infiltration and metastasis to other sites, mitotic count > 1-5 per 10 high-powered fields, and most recently, mutation in the c-kit gene. Surgical resection remains the mainstay of treatment, as chemotherapy and radiation are ineffective. Long-term follow-up is imperative, as recurrence rates are high.

Evolution of sentinel lymph node biopsy for melanoma at a National Cancer Institute-designated cancer center.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has rapidly evolved into the standard of care for clinically node-negative melanoma. Since adopting sentinel lymph node (SLN) technology in 1993, we have periodically reviewed our institution's results and made several modifications. METHODS: From January 1993 to December 1998, 182 patients with clinically node-negative primary cutaneous melanoma underwent SLNB. Charts were retrospectively reviewed and assessed for the technique for the identification of the SLN, the pathologic analysis, and the use of intraoperative frozen section. RESULTS: The accuracy of SLN identification improved from 91% to 100% with the combination of isosulfan blue dye and radiolabeled colloid over isosulfan blue dye alone. Routine versus selective lymphoscintigraphy identified 7 in-transit SLNs and increased detection of dual nodal basin drainage (15%-27%). Identification of micrometastases in the SLN increased from 14% to 24% after a modification of pathologic evaluation. The positive SLN was the only involved node in most patients (80%). Intraoperative frozen section had a sensitivity of 58% and was of benefit in only 13 of 124 patients (10%). CONCLUSIONS: Several modifications to the identification of the SLNs and the detection of metastatic melanoma have improved our outcome with SLNB. A careful, periodic review of results to identify areas for improvement at each institution is crucial to the success of SLNB for melanoma.

Pathologic and clinical features influencing outcome of thin cutaneous melanoma: correlation with newly proposed staging system.

The incidence of malignant melanoma is increasing. Because of increased awareness, early recognition of malignant melanoma has become more common. In 1997, a new staging system for cutaneous melanoma was proposed, with reclassification of thin melanoma < 1 mm, with and without ulceration. This report evaluates the pathologic and clinical features of thin melanomas influencing recurrence and survival from a tertiary cancer center in an attempt to correlate findings with the proposed staging system. A review of the Roswell Park Cancer Institute tumor registry identified 352 patients with thin cutaneous melanomas (< 1.0 mm) seen during an 18-year period ending August 30, 1998. Overall survival was 93 and 87 per cent at 5 and 10 years, respectively. Disease-free survival was 94 and 93 per cent at 5 and 10 years, respectively. Local recurrence occurred in 3 per cent of patients, regional recurrence in 3 per cent, and metastatic disease in 3 per cent, for an overall recurrence of 7 per cent, with a median follow-up of 118 months. Only the presence of ulceration was a significant prognostic factor for recurrence by both univariate and multivariate analysis. Failure rates (any recurrence) by Clark levels I, II, and III/IV were 3, 5, and 10 per cent, respectively (P = 0.14). Failure rates by tumor thickness (mm), for 0.0-0.24, 0.25-0.49, 0.50-0.74, and 0.75-0.99 were 3, 4, 7, and 10 per cent, respectively (P = 0.49). Ten-year disease-free survival for ulceration versus no ulceration was 40 and 94 per cent, respectively (P < 0.0001). We conclude that thin cutaneous melanoma carries an excellent prognosis with appropriate treatment. Our findings support inclusion of ulceration in a new staging system. Lesions 0.76 to 0.99 mm and Clark level III and IV may warrant close observation as a separate subgroup.

Clinical importance of late recurrence in soft-tissue sarcomas.

BACKGROUND AND OBJECTIVES: Soft-tissue sarcomas (STS) represent a diverse histologic group of malignancies at risk for local and distant failure. We studied the impact of late (5 or more years) vs. early recurrence (less than 5 years) on subsequent outcome. METHODS: Four hundred sixty-eight patients with STS treated between 1962 and 1992 were evaluated for late (n = 39; 8%) or early (n = 253; 54%) recurrence. Clinical and pathologic factors were reviewed. Survival data were analyzed by the Kaplan-Meier method and the log-rank test. RESULTS: Of the 39 patients with a late recurrence (median follow-up 156 months), 18 patients had local recurrence, 7 patients developed distant recurrence, and 14 patients had local and distant recurrence. Thirty patients with late local and/or distant recurrence underwent complete or wide excision (n = 16), amputation (n = 4), or local resection (n = 10). The overall 5-year survival rate following late recurrence was 61%. The 5-year overall survival rate was statistically better for patients with a late local recurrence alone than for patients with distant failure, 94% vs. 36%, respectively (P = 0.003). Neither the site of the primary STS, age, primary margin status, nor histology had any effect on subsequent local or distant failure and subsequent survival. CONCLUSIONS: These data suggest that an aggressive approach is appropriate in patients who present with late recurrence (more than 5 years) following treatment of the primary STS. Impressive survival rates can be achieved in the treatment of local recurrences.

Primary extremity sarcoma: what is the appropriate follow-up?

BACKGROUND: Our objective was to evaluate the effectiveness of follow-up tests for detecting first local and distant recurrences in patients with primary extremity soft tissue sarcoma. METHODS: We retrospectively analyzed all adult cases of primary extremity soft tissue sarcoma (n = 174) treated between 1982 and 1992. Patients were observed every 3 months for 2 years, every 4 months the third year, every 6 months the next 2 years, and annually, thereafter. Each visit consisted of taking the patient's history, a physical examination, a complete blood count, a blood chemistry panel, and a chest x-ray. For high-grade tumors, the primary site was imaged annually when clinically appropriate. RESULTS: Of 141 patients who were assessable, 29 patients developed local recurrence and 57 developed distant recurrence. All but one of the local recurrences was detected on the basis of an abnormal physical examination. Of the 29 patients who developed local recurrence, 25 were resected. Distant metastases were detected because of symptoms in 21 cases. Of the 36 asymptomatic lung recurrences, 30 were detected by follow-up chest x-ray. Of the 36 asymptomatic lung recurrences, 24 patients underwent metastasectomy. The positive and negative predictive values of surveillance chest x-ray were 92% and 97%, respectively. Laboratory testing never led to the detection of recurrence. CONCLUSIONS: Close surveillance by clinical assessment and chest x-ray is appropriate for follow-up observation of patients with primary extremity soft tissue sarcoma.

Current follow-up strategies after potentially curative resection of extremity sarcomas: results of a survey of the members of the society of surgical oncology.

BACKGROUND: The follow-up of patients after potentially curative resection of extremity sarcomas has significant clinical and fiscal implications. However, the ideal postoperative surveillance regimen for these uncommon neoplasms remains ill-defined. This study was designed to determine the current follow-up practices of a large, diverse group of physicians who care for sarcoma patients. METHODS: The 1592 members of the Society of Surgical Oncology (SSO) were surveyed regarding their follow-up practices with a detailed questionnaire mailed in 1997. Information regarding frequency of follow-up testing was requested for extremity sarcoma patients treated for cure based on 4 vignettes: low grade lesion 5 cm and high grade lesion 5 cm. Respondents were asked to indicate the number of office visits, laboratory tests and imaging studies performed annually during the first 5 years and the 10th year after surgery. RESULTS: Forty-five percent (716 of 1592) completed the survey. Of the 343 respondents who performed sarcoma surgery, 318 (93%) also provided long term postoperative follow-up for their patients. Ninety-four percent of respondents (295 of 318) were trained in general surgery and 5% (15 of 318) completed orthopedic residencies. Ninety-one percent (291 of 318) were also fellowship trained (80% in surgical oncology). Sixty-three percent (201 of 318) were in academic practice. Routine office visits and chest X-ray (CXR) were the most frequently performed items for each of the years. The frequency of office visits and CXR increased with tumor size and grade and decreased with postoperative year. Complete blood count and liver function tests were the most commonly ordered blood tests, but many respondents did not order any blood tests routinely. Imaging studies of the extremities were performed on the majority of patients with large (> 5 cm) low grade lesions and on both large and small high grade lesions during the first postoperative year. CONCLUSIONS: Postoperative sarcoma surveillance strategies utilized by members of the SSO rely most heavily on office visits and CXR. Tumor grade, tumor size, and postoperative year affect surveillance intensity.

Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: long-term results of radiation therapy oncology group protocol 89-02.

PURPOSE: To assess the outcome of a multi-institutional, national cooperative group study attempting functional preservation of the anorectum for patients with limited, distal rectal cancer. METHODS AND MATERIALS: Between September 21, 1989 and November 1, 1992, a Phase II trial of sphincter-sparing therapy was conducted for patients with clinically mobile rectal cancers located below the pelvic peritoneal reflection. Protocol treatment was designed for patients who were, in the judgement of their attending surgeon, unsuitable for anal sphincter conservation in the context of anterior resection, and would have required abdominoperineal resection (APR) as conventional surgical therapy. Primary cancers were estimated to be 4 cm or less in largest clinical diameter, and occupied 40% or less of the rectal circumference. Chest radiography and computerized axial tomography (CT) of the abdomen and pelvis excluded patients with overt lymphatic or hematogenous metastases. Protocol surgery was intended to remove the primary cancer by en-bloc, transmural excision of an ellipse of rectal wall by transanal, transcoccygeal, or trans-sacral technique, while conserving the anal sphincter. Based on tumor size, T classification, grade, and adequacy of surgical margins, patients were allocated to one of three treatment assignments: observation, or adjuvant treatment with 5-fluorouracil (5-FU) and one of two different dose levels of local-regional radiation. After completion of protocol therapy, patients were observed with follow-up that included periodic general physical and rectal examination, determinations of CEA, abdominopelvic CT, chest radiography, and surveillance endoscopy. Sixty-five eligible and analyzable patients were registered. RESULTS: With minimum follow-up of 5 years and median follow-up of 6.1 years, 11 patients have failed: 3 patients recurred local-regionally only, 3 patients had distant failure alone, and 5 patients manifested local-regional and distant failure. Eight patients died of intercurrent illness. Local-regional failure correlated with T-category revealed: T1 1/27 (4%), T2 4/25 (16%), and T3 3/13 (23%). Local-regional failure escalated with percentage involvement of the rectal circumference: 2/31 (6%) among patients with cancers involving 20% or less of the rectal circumference, and 6/34 (18%) among patients with cancers involving 21-40% of the circumference. Distant dissemination rose with T-category with 1/27 (4%) T1, 3/25 (12%) T2, and 4/13 (31%) T3 patients manifesting hematogenous spread. Eight patients (12%) required temporary or permanent colostomy. Five of 8 patients with local-regional recurrence achieved local-regional control with management including surgery, although 4 of these patients subsequently developed distant dissemination. Three patients (5%) had persistent, uncontrolled, local disease. Actuarial freedom from pelvic relapse at 5 years is 88% based on the entire study population, and 86% for the less favorable patients treated with adjuvant radiation and 5-FU. CONCLUSION: Conservative, sphincter-sparing therapy is a feasible alternative treatment for selected patients with limited cancer involving the middle and lower rectum. Risk of both local and distant failure appears to escalate with increasing T-category (depth of invasion). Results achieved in the multi-institutional, cooperative group setting approximate results reported from single institutions.

Nodal basin recurrence following lymph node dissection for melanoma: implications for adjuvant radiotherapy.

PURPOSE: To analyze patterns of failure in malignant melanoma patients with lymph node involvement who underwent complete lymph node dissection (LND) of the nodal basin. To determine prognostic factors predictive of local recurrence in the lymph node basin in order to select patients who may benefit from adjuvant radiotherapy. METHODS AND MATERIALS: A retrospective analysis of 338 patients undergoing complete LND for melanoma between 1970 and 1996 who had pathologically involved lymph nodes was performed. Mean follow-up from the time of LND was 54 months (range: 12-306 months). Lymph node basins dissected included the neck (56 patients), axilla (160 patients), and groin (122 patients). Two hundred fifty-three patients (75%) underwent therapeutic LND for clinically involved nodes, while 85 patients (25%) had elective dissections. Forty-four percent of patients received adjuvant systemic therapy. No patients received adjuvant radiotherapy to the lymph node basin. RESULTS: Overall and disease-specific survival for all patients at 10 years was 30% and 36%, respectively. Overall nodal basin recurrence was 30% at 10 years. Mean time to nodal basin recurrence was 12 months (range: 2-78 months). Site of nodal involvement was prognostic with 43%, 28%, and 23% nodal basin recurrence at 10 years with cervical, axillary, and inguinal involvement, respectively (p = 0.008). Extracapsular extension (ECE) led to a 10-year nodal basin failure rate of 63% vs. 23% without ECE (p < 0.0001). Patients undergoing a therapeutic dissection for clinically involved nodes had a 36% failure rate in the nodal basin at 10 years, compared to 16% for patients found to have involved nodes after elective dissection (p = 0.002). Lymph nodes larger than 6 cm led to a failure rate of 80% compared to 42% for nodes 3-6 cm and 24% for nodes less than 3 cm (p < 0.001). The number of lymph nodes involved also predicted for nodal basin failure with 25%, 46%, and 63% failure rates at 10 years for 1-3, 4-10, and > 10 nodes involved (p = 0.0001). There was no significant difference in nodal basin control in patients with synchronous or metachronous lymph node metastases, nor in patients receiving or not receiving adjuvant systemic therapy. Nodal basin failure was predictive of distant metastasis with 87% of patients with nodal basin recurrence developing distant disease compared to 54% of patients without nodal failure (p < 0.0001). On multivariate analysis, number of positive nodes and type of dissection (elective vs. therapeutic) were significant predictors of overall and disease-specific survival. Size of the largest lymph node was also predictive of disease-specific survival. Site of nodal involvement and ECE were significant predictors of nodal basin failure. CONCLUSIONS: Malignant melanoma patients with nodal involvement have a significant risk of nodal basin failure after LND if they have cervical involvement, ECE, >3 positive lymph nodes, clinically involved nodes, or any node larger than 3 cm. Patients with these risk factors should be considered for adjuvant radiotherapy to the lymph node basin to reduce the incidence of nodal basin recurrence. Patients with nodal basin failure are at higher risk of developing distant metastases.

Accuracy of pathologic techniques for the diagnosis of metastatic melanoma in sentinel lymph nodes.

BACKGROUND: Sentinel lymph node (SLN) biopsy can accurately predict the presence of metastatic melanoma (MM) and has been used to identify patients with occult metastases. We present an analysis of the sensitivity and specificity of standard pathological techniques including intraoperative frozen section, permanent section, and immunohistochemistry in diagnosing MM within the SLN. METHODS: Sixty-nine consecutive patients with primary malignant melanoma thickness of >1.0 mm or thinner lesions invading the reticular dermis (Clark level IV) who underwent SLN biopsy were reviewed. Lymph nodes were examined intraoperatively by frozen section (FS), permanent section (H&E), and by immunohistochemistry (IH) for S-100 protein and HMB45. RESULTS: MM was found in 14 of 69 cases (20%). Permanent section H&E was performed in all cases, FS in 64 cases, and IH in 65 cases. FS analysis diagnosed MM in 4 of 14 cases (29%), was suspicious in 2 of 14 (14%), and falsely negative (FN) in 8 of 14 (57%) ultimately found to be positive with further workup. Within the FN group, MM was identified on review of the original FS slides in 3 of 8 cases (38%). Furthermore, within the FN group, the remaining 5 cases were identified as positive for MM by either permanent and/or deeper H&E sections and IH. IH alone with permanent H&E sections would have diagnosed MM in only 8 of 10 cases (80%) that were FS negative or suspicious. In no cases was MM identified by IH alone with the permanent and deeper H&E sections being negative. It is noteworthy that no false-positive cases were identified. CONCLUSIONS: Intraoperative FS has low sensitivity in identifying MM within the SLN. IH alone does not increase the diagnostic yield. A combination of permanent H&E sections with deeper levels and S-100 and HMB45 IH dramatically increases the overall diagnostic sensitivity of SLN biopsy. Definitive diagnosis should await permanent H&E sections and IH staining.