Ralph J. Tuthill

Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: Overall results of a randomized trial of the Southwest Oncology Group

PURPOSE Patients with clinically negative nodes constitute over 85% of new melanoma cases. There is no adjuvant therapy for intermediate-thickness, node-negative melanoma patients. PATIENTS AND METHODS The Southwest Oncology Group conducted a randomized phase III trial of an allogeneic melanoma vaccine for 2 years versus observation in patients with intermediate-thickness (1.5 to 4.0 mm or Clarks level IV if thickness unknown), clinically or pathologically node-negative melanoma (T3N0M0). RESULTS Six hundred eighty-nine patients were accrued over 4.5 years; 89 patients (13%) were ineligible. Surgical node staging was performed in 24%, the remainder were clinical N0. Thirteen eligible patients refused assigned treatment: seven on the observation arm and six on the vaccine arm. Most vaccine patients experienced mild to moderate local toxicity, but 26 (9%) experienced grade 3 toxicity. After a median follow-up of 5.6 years, there were 107 events (tumor recurrences or deaths) among the 300 eligible patients randomized to vaccine compared with 114 among the 300 eligible patients randomized to observation (hazard ratio, 0.92; Cox-adjusted P(2) = 0.51). There was no difference in vaccine efficacy among patients with tumors < or = 3 mm or > 3 mm. CONCLUSION This represents one of the largest randomized, controlled trials of adjuvant vaccine therapy in human cancer reported to date. Compliance with randomization was excellent, with only 2% refusing assigned therapy. There is no evidence of improved disease-free survival among patients randomized to receive vaccine, although the power to detect a small but clinically significant difference was low. Future investigations of adjuvant vaccine approaches for patients with intermediate-thickness melanoma should involve larger numbers of patients and ideally should include sentinel node biopsy staging.

CD34 and factor-XIIIa immunoreactivity in dermatofibrosarcoma protuberans and dermatofibroma.

The histologic distinction between dermatofibrosarcoma protuberans (DFSP) and the fibrous type of benign fibrous histiocytoma (dermatofibroma, DF) may be extremely difficult. In this study, we evaluated the extent and pattern of immunoreactivity of both CD34 and factor XIIIa in a large number of DFSPs and DFs in order to determine the utility of these markers in their distinction. Using histologic criteria alone, the authors independently evaluated and agreed upon 30 cases of DF and 24 cases of DFSP, and a representative section was stained with antibodies to both factor XIIIa and CD34. Immunopositivity was evaluated semiquantitatively and assigned a score from 0 to 5. CD34 immunoreactivity was seen in 22 (92%) of 24 DFSPs (mean CD34 score, 4.60 +/- 0.3). Only 12 (40%) of 30 DFs showed CD34 immunopositivity (mean CD34 score, 0.6 +/- 0.1). Factor XIIIa was seen in 29 (97%) of 30 DFs (mean factor-XIIIa score, 4.1 +/- 0.3). In contrast, 18 (75%) of 24 DFSPs stained for factor XIIIa (mean factor-XIIIa score, 1.3 +/- 0.2), but in most of these cases the factor-XIIIa-positive cells were felt to be entrapped nonneoplastic dermal dendrocytes. Thus, an immunoprofile using antibodies to CD34 and factor XIIIa is capable of distinguishing between DFSP and the fibrous type of DF in the vast majority of cases, as long as there is recognition that there may be some CD34-positive cells in DFs, as well as some factor-XIIIa-positive cells in DFSPs.

Squamous cell carcinoma of the nail bed: a clinicopathological study of 12 cases

Twelve cases were reviewed of squamous cell carcinoma of the nail bed, with emphasis on the aetiological role of human papillomavirus (HPV) infection and radiation damage. Using a hybridization technique, similar HPV genomes were detected in a uterine cervical neoplasia and a subungual squamous cell carcinoma in the same patient.

Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma

Clear cell sarcoma of soft tissue (malignant melanoma of soft parts) is a soft tissue sarcoma with melanocytic differentiation that typically occurs in the tendons and aponeuroses of young adults. As demonstrated by cytogenetics and reverse-transcriptase polymerase chain reaction, between 70% and over 90% of clear cell sarcomas have a t(12;22) translocation, fusing the EWS and ATF1 genes on chromosomes 22q12 and 12q13, respectively. Identification of this translocation distinguishes clear cell sarcoma from histologic mimics, most importantly conventional malignant melanoma. We report our experience with a commercially available, dual-color, break-apart fluorescence in situ hybridization (FISH) probe, which allows detection of EWS (22q12) gene rearrangement in formalin-fixed, paraffin-embedded tissues. Histologically and immunophenotypically well-characterized cases of clear cell sarcoma (n=10) and malignant melanoma (n=32) were evaluated with a 22q12 dual-color, break-apart probe (Vysis, Downers Grove, IL, USA), which spans the known common breakpoints in the EWS gene on chromosome 22 (introns 7–10). Signals from tumor cell nuclei were counted under a fluorescence microscope and the presence of red–green break-apart signals was recorded. Of the clear cell sarcoma cases, seven of 10 showed evidence of an EWS gene rearrangement with a mean of 81.6% positive cells per sample (range: 60–95%). All cases of malignant melanoma (n=32) showed virtually absent break-apart signals in the EWS gene (less than 4% cells per case). FISH detects EWS gene rearrangement in a substantial proportion of clear cell sarcomas, with excellent specificity. Importantly, EWS FISH is negative in malignant melanoma, a clinically dissimilar tumor, which may closely mimic clear cell sarcoma histologically and immunohistochemically. As the studied probe can be utilized in routinely processed tissue, FISH provides an excellent alternative to reverse-transcriptase polymerase chain reaction in cases where fresh tissue is unavailable.

A phase 2 trial of complete resection for stage IV melanoma: Results of Southwest Oncology Group Clinical Trial S9430

BACKGROUND On the basis of retrospective experience at individual centers, it appears that patients with stage IV melanoma who undergo complete resection have a favorable outcome compared with patients with disseminated stage IV disease. The Southwest Oncology Group (SWOG) performed a prospective trial in patients with metastatic melanoma who were enrolled before complete resection of their metastatic disease and provided prospective outcomes in the cooperative group setting. METHODS Based on their physical examination and radiologic imaging studies, patients with a stage IV melanoma judged amenable to complete resection underwent surgery within 28 days of enrollment. All eligible patients were followed with scans (computed tomography or positron emission tomography) every 6 months until relapse and death. RESULTS Seventy-seven patients were enrolled from 18 different centers. Of those, 5 patients were ineligible; 2 had stage III disease alone; and 3 had no melanoma in their surgical specimen. In addition, 8 eligible patients had incompletely resected tumor. Therefore, the primary analysis included 64 completely resected patients. Twenty patients (31%) had visceral disease. With a median follow-up of 5 years, the median relapse-free survival was 5 months (95% CI, 3-7 months) whereas median overall survival was 21 months (95% CI, 16-34 months). Overall survivals at 3 and 4 years were 36% and 31%, respectively. CONCLUSIONS In a prospective multicenter setting, appropriately selected patients with stage IV melanoma achieved prolonged overall survival after complete surgical resection. Although median relapse-free survival was only 5 months, patients could still frequently undergo subsequent surgery for isolated recurrences. This patient population is appropriate for aggressive surgical therapy and for trials evaluating adjuvant therapy.

Risk assessment in localized primary cutaneous melanoma: A Southwest Oncology Group study evaluating nine factors and a test of the Clark logistic regression prediction model

We studied 9 clinical and pathologic factors in 259 patients using Cox model regression analysis to determine which factors have independent predictive value. Median follow-up time in all patients still alive was 12.3 years (range, 1.7 to 16.7 years). Tumor-infiltrating lymphocytes (P = .005), primary site (P = .006), and thickness (P = .02) had independent predictive value. Ulceration (P = .06) and age (P = .07) had marginal value. We used 6 of those factors to test the Clark logistic regression prediction model, which accurately predicted 8-year survival in 121 (72.9%) of 166 patients and accurately predicted melanoma-specific mortality in 32 (43%) of 74 patients. The combined or overall accuracy of the Clark model was only 64%.

Comprehensive analysis of 112 melanocytic skin lesions demonstrates microsatellite instability in melanomas and dysplastic nevi, but not in benign nevi

Introduction: Alterations in the length of DNA repetitive sequences (microsatellite instability (MSI)) represent distinct tumorigenic pathways associated with several familial and sporadic tumors.

Abnormal Colonic Motility in Progressive Systemic Sclerosis

Progressive systemic sclerosis alters smooth muscle function throughout the gastrointestinal tract. In 10 consecutive patients with the disease, colonic spike activity and contractile activity were measured after a 1000-kcal meal, intramuscular injection of neostigmine, or intravenous injection of metoclopramide. The 1000-kcal meal stimulated a significant increase in spike and contractile activity in normal subjects. Nine of the 10 patients had no increase in motility after eating. Neostigmine or metoclopramide stimulated colonic spike (p less than 0.01) and contractile (p less than 0.02) activity in normal subjects and stimulated colonic motility (p less than 0.01) in four of 10 patients with less severe systemic manifestations of the disease (Group 1). The drugs had no effect on patients with severe progressive systemic sclerosis (Group II). The patients with severe scleroderma had significant gastrointestinal roentgenographic abnormalities and severe cardiac, renal, or pulmonary dysfunction. Four of six Group II patients died from the disease; all four had marked smooth muscle atrophy in the colonic wall. These findings suggest that the gastrocolonic response is absent early in the disease process and that the smooth muscle atrophy occurring with progression of the disease may lead to a more severe colonic motor disturbance.

Malignant melanoma arising in a blue nevus with features of pilar neurocristic hamartoma

A 65‐year‐old man presented with a history of a giant blue plaque of the parietal scalp since childhood. Biopsy revealed a cellular blue nevus. The blue nevus was observed for 10 years and thought to be unchanged until a new adjacent lesion was noted. Biopsy of the new lesion revealed metastatic malignant melanoma. A wide excision was performed of the original lesion which revealed malignant melanoma arising in a blue nevus. Areas within the blue nevus were consistent with a pilar neurocristic hamartoma, whereas other areas were consistent with a common blue nevus. Subsequent satellite metastases developed, with early metastases resembling blue nevi except for the absence of a stromal component and the presence of hyperchromatic nuclei. Later metastases were typical of metastatic melanoma. This case illustrates the uncommon evolution of malignant melanoma from a blue nevus. The histological features and relationship between melanoma, blue nevus, and pilar neurocristic hamartoma are reviewed.

Minocycline-related cutaneous hyperpigmentation as demonstrated by light microscopy, electron microscopy and X-ray energy spectroscopy

Argenyi ZB, Finelli L, Bergfeld WF, Tuthill RJ, McMahon JT, Ratz JL, Pefroff N. Minocycline‐related cutaneous hyper‐pigmentation as demonstrated by light microscopy, electron microscopy and X‐ray energy spectroscopy.