Vascular involvement in the prognosis of primary cutaneous melanoma.

OBJECTIVE: To examine the role of vascular invasion as a prognostic factor in melanoma. DESIGN: Retrospective survival analysis. SETTING: Academic medical center. PATIENTS: A total of 526 patients with primary cutaneous melanoma from the University of California, San Francisco, Melanoma Center database with 2 years of follow-up or documented relapse. MAIN OUTCOME MEASURES: (1) Presence of vascular involvement defined as vascular invasion with tumor cells within blood or lymphatic vessels; or uncertain vascular invasion, with melanoma cells immediately adjacent to the endothelium. (2) Percentage with metastasis or death and relapse-free and overall survival. RESULTS: The presence of either type of vascular involvement significantly increased the risk of relapse and death and reduced the survival associated with melanoma. The impact of vascular involvement on these outcomes was similar to that of ulceration. In a multivariate analysis, vascular involvement was the second most important factor (after tumor thickness) in the primary tumor in predicting survival. CONCLUSIONS: Vascular involvement is an important independent predictor of metastasis and survival in melanoma. The phenomenon of uncertain vascular invasion describes an earlier step than definite vascular invasion in tumor progression.

Micrometastasis to in-transit lymph nodes from extremity and truncal malignant melanoma.

BACKGROUND: The sentinel lymph node (SLN) is the first lymph node in the regional nodal basin to receive metastatic cells. In-transit nodes are found between the primary melanoma site and regional nodal basins. To date, this is one of the first reports on micrometastasis to in-transit nodes. METHODS: Retrospective database and medical records were reviewed from October 21, 1993, to November 19. 1999. At the UCSF Melanoma Center, patients with tumor thickness > 1 mm or < 1 mm with high-risk features are managed with preoperative lymphoscintigraphy, selective SLN dissection, and wide local excision. RESULTS: Thirty (5%) out of 557 extremity and truncal melanoma patients had in-transit SLNs. Three patients had positive in-transit SLNs and negative SLNs in the regional nodal basin. Two patients had positive in-transit and regional SLNs. Three patients had negative in-transit SLNs but positive regional SLNs. The remaining 22 patients were negative for in-transit and regional SLNs. CONCLUSIONS: In-transit SLNs may harbor micrometastasis. About 10% of the time, micrometastasis may involve the in-transit and not the regional SLN. Therefore, both in-transit and regional SLNs should be harvested.

Evaluation of sentinel lymph node status in spindle cell melanomas.

BACKGROUND: The propensity for spindle cell melanoma to metastasize to the lymph node is relatively low despite its relative thick depth. To date, there are no published reports on the sentinel lymph node (SLN) status in patients diagnosed with spindle cell melanoma and desmoplastic malignant melanoma (DMM). OBJECTIVE: Our purpose was to report our experience on the SLN status in spindle cell melanoma and DMM. METHODS: We undertook a retrospective database and medical record review from Oct 21, 1993 to Sept 29, 1999. At the University of California at San Francisco Melanoma Center, patients with tumor thickness greater than 1 mm or less than 1 mm with high-risk features are managed with preoperative lymphoscintigraphy, selective SLN dissection, and wide excision. RESULTS: Of 29 patients diagnosed with spindle cell melanoma and DMM, 28 had negative SLNs and are free of disease except for one patient who experienced splenic, bony, and brain metastases. The mean follow-up in this population was 16.5 and 11 months, respectively. CONCLUSION: Our preliminary findings show that SLNs from patients diagnosed with spindle cell melanoma and DMM only rarely harbor micrometastasis despite their relative thickness. A larger number of cases from multicenter databases may further define the true biology of SLNs in this melanoma variant.

Fine needle aspiration in the diagnosis of metastatic melanoma.

BACKGROUND: Fine needle aspiration is an accurate technique to diagnose metastatic melanoma. Few reports exist in the literature describing its usefulness in many patients with melanoma confirmed by open biopsy. OBJECTIVE: The purpose of this study was to determine the utility and predictive value of fine needle aspiration in patients with malignant melanoma who presented with lesions suspected to be metastatic. METHODS: We retrospectively reviewed 99 cases of fine needle aspiration and the corresponding histologic findings obtained by open biopsy in 82 patients. RESULTS: Of the 99 cases, 86 were positive for melanoma, 12 were negative, and one was indeterminate. The positive predictive value of fine needle aspiration was 99%. One patient had a false-positive diagnosis. CONCLUSION: Fine needle aspiration is a rapid, accurate, and minimally invasive procedure that is useful in the diagnosis of metastatic melanoma. Patients with a positive aspirate of palpable regional nodes can proceed directly to surgery, bypassing the need for an open biopsy.

Outpatient combination chemoimmunotherapy for patients with metastatic melanoma. Results of a phase I/II trial.

BACKGROUND: Few studies have examined the feasibility, safety, and efficacy of an outpatient biochemotherapy regimen of low dose, subcutaneously administered interleukin-2 (IL-2) for patients with metastatic (Stage IV) melanoma. METHODS: Nineteen patients were treated with intravenous cisplatin and dacarbazine (DTIC), oral tamoxifen, and subcutaneous IL-2 and interferon-alpha-2b (IFN). Eligibility requirements included bidimensionally measurable metastatic melanoma, a Karnofsky performance score of 60 or higher, absence of significant cardiac or pulmonary dysfunction, no prior DTIC or cisplatin chemotherapy, and no evidence of central nervous system involvement. Patients were given a minimum of 2 6-week cycles. Treatment was continued in the absence of progressive disease, and patients were monitored for response at two-cycle intervals. RESULTS: Of the 19 patients, 1 (5%) achieved a complete response; 6 (32%) a partial response; 3 (16%) stable disease; and 9 (47%) progressive disease, for an overall response proportion of 37% (95% confidence interval, 16-61%). The median survival of the treated cohort was 10.6 months. The mean time to disease progression for patients with stable disease or better was 8.4 months, with a mean response duration of 5.1 months. The most common toxicities noted were constitutional symptoms, weight loss, nausea, neutropenia, and fatigue. The 19 patients received a total of 59 cycles of treatment, and IL-2, IFN, or both were held in 14 of these cycles secondary to Grade 3 or 4 toxicities. In addition, six patients required dose reduction of IL-2 and/or IFN. CONCLUSIONS: Chemoimmunotherapy consisting of cisplatin, DTIC, and tamoxifen combined with subcutaneous IL-2 and IFN can be safely administered in an outpatient setting. The described regimen yields moderate activity in metastatic melanoma, and efforts to improve its efficacy merit further examination.

Recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) and autologous melanoma vaccine mediate tumor regression in patients with metastatic melanoma.

In mice, significant immunoprotection was achieved using B16 melanoma cells transfected with granulocyte-macrophage colony-stimulating factor (GM-CSF) as vaccines (Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993;90:3539-43). The aim of this study is to test the hypothesis that recombinant human GM-CSF (rhGM-CSF) injected with autologous melanoma vaccine may result in tumor rejection in melanoma patients. Twenty stage IV melanoma patients were treated as outpatients with multiple cycles of autologous melanoma vaccine and bacillus Calmette-Guérin (BCG) plus rhGM-CSF injection in the vaccine sites. Two patients (10%) showed a complete response, with one patient showing resolution of subcutaneous, hepatic, and splenic metastases. In the second patient, buccal, subcutaneous, pulmonary, paraaortic, hepatic, splenic, and retroperitoneal metastases regressed completely. Two patients (10%) showed partial response, with regression of a paraaortic metastasis in one patient. In the second patient, there was shrinkage (> 75%) of a large hepatic lesion. One patient has been rendered free of disease after resection of a single pulmonary metastatic nodule. Three patients (15%) had stable disease during treatment but subsequently developed progression of disease. In 12 patients (60%), the disease progressed. Side effects were minimal. In a separate pilot study, 15 stage IV melanoma patients were also treated with autologous melanoma vaccine with BCG but not with rhGM-CSF; none responded. The fact that four patients showed objective responses to active specific immunotherapy with rhGM-CSF demonstrates that melanoma patients bearing a significant tumor burden may respond specifically to their autologous melanoma.

Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma.

OBJECTIVE: To develop a prognostic model, based on clinical and pathological data, to estimate the probability of micrometastasis in the sentinel lymph node in patients with malignant melanoma. DESIGN: Retrospective analytical study. SETTING: University medical center. PATIENTS: Two hundred fifteen patients with American Joint Committee on Cancer stages I and II cutaneous malignant melanoma underwent sentinel lymph node biopsy. MEASUREMENTS: Presence of microscopic melanoma in the sentinel lymph node(s). Clinical attributes recorded included age, sex, and location of the primary melanoma. Pathological attributes recorded before lymph node evaluation included ulceration, microsatellites, angiolymphatic invasion, mitotic rate, tumor infiltrating lymphocytes, and regression. RESULTS: Forty-six patients (21.4%) overall had a positive sentinel lymph node. Patients with tumor thickness ranging from 3.0 to 3.9 mm had the highest incidence (50%) of nodal involvement, followed by those with tumors 4.0 to 4.9 mm thick (41%). Patients with melanomas measuring greater than 4.9 mm thick and those between 1.0 and 2.9 mm had a similar rate of nodal involvement (16%-17%). Clinical characteristics had minimal correlation with nodal status in multivariate analysis. The total number of histological high-risk features was significantly correlated with sentinel lymph node involvement. Important pathological risk factors included ulceration, high mitotic rate, angiolymphatic invasion, and microsatellites. Patients with tumor thickness greater than 1.0 mm but lacking these features had a 14% risk of occult metastases. CONCLUSION: Among patients with clinically node-negative primary melanoma, the presence of 1 or more high-risk histological features significantly increases the incidence of microscopic nodal involvement and can be used to predict the likelihood of a positive sentinel lymph node biopsy.

Optimal selective sentinel lymph node dissection in primary malignant melanoma.

OBJECTIVE: To determine the optimal approach of selective sentinel lymph node (SLN) dissection in primary malignant melanoma. DESIGN: Consecutive patient study. Prior to selective SLN dissection and wide local excision of the primary melanoma biopsy site, technetium Tc 99m sulfur colloid was injected intradermally around the primary melanoma or biopsy site to mark the SLN. Isosulfan blue (Lymphazurin, Hirsch Industries Inc, Richmond, Va) was injected at the primary biopsy site immediately before the surgical procedure. SETTING: Teaching hospital tertiary care referral center. MAIN OUTCOME MEASURES: Successful identification of SLNs being defined as positive for microscopic metastatic melanoma by blue dye staining, radioisotope uptake, or both. RESULTS: Selective intraoperative mapping by gamma probe and visualization of blue dye-stained SLN(s) resulted in a 98% (160/163) successful identification rate. Thirty patients (18.4%) had microscopic metastatic melanoma of the SLN(s), 22 of whom had subsequently completed lymphadenectomy. In 4 (18.2%) of these 22 patients, further microscopic metastatic disease was found in 1 of 8 nodes, 1 of 8 nodes, 1 of 28 nodes, and 1 of 9 nodes. No notable complications were encountered. Five recurrent cases from patients with SLNs without microscopic metastatic melanoma (3.8%) and 2 from patients with SLNs with microscopic metastatic melanoma (6%) were found during a median follow-up period of 463 days. A second primary melanoma developed in 2 patients; neither had no local recurrence. CONCLUSIONS: Sequential combination of preoperative lymphoscintigraphy and intraoperative mapping is a reliable way to identify regional SLN. The frequency of microscopic metastatic melanoma of the SLN(s) is 18.4%. Gamma-probe--guided resection minimizes the extent of lymph node dissection. Further follow-up is needed to assess the outcome of this group of patients for regional and systemic recurrences.

Clinically recognized dysplastic nevi. A central risk factor for cutaneous melanoma.

OBJECTIVE: To investigate the relationship of number and type of nevi to the development of melanoma. DESIGN: Case-control study. SETTING: Outpatient clinics in referral hospitals. PATIENTS: Cases were 716 consecutive patients with newly diagnosed melanoma identified at 2 melanoma centers between January 1, 1991, and December 31, 1992. Stratified random sampling of patients from outpatient clinics was used to identify 1014 participating controls of the same age, sex, race, and geographic distribution as the melanoma cases. All study subjects underwent an interview, a complete skin examination, photography of the most atypical nevi, and, if the patient was willing, a biopsy of the most atypical nevus. MAIN OUTCOME MEASURES: Number and type of nevi on the entire body were systematically reported. All diagnoses of clinically dysplastic nevi were confirmed by expert examiners. RESULTS: Risk for melanoma was strongly related to number of small nevi, large nondysplastic nevi, and clinically dysplastic nevi. In the absence of dysplastic nevi, increased numbers of small nevi were associated with an approximately 2-fold risk, and increased numbers of both small and large nondysplastic nevi were associated with a 4-fold risk. One clinically dysplastic nevus was associated with a 2-fold risk (95% confidence interval, 1.4-3.6), while 10 or more conferred a 12-fold increased risk (95% confidence interval, 4.4-31). Congenital nevi were not associated with increased risk of melanoma. CONCLUSIONS: Although nondysplastic nevi confer a small risk, clinically dysplastic nevi confer substantial risk for melanoma. On the basis of nevus number and type, clinicians can identify a population at high risk of this epidemic cancer for screening and intervention.

Unusual variants of melanoma: fact or fiction?

Evidence is reviewed separating unusual variants of melanoma from the large group of superficial spreading and nodular (SSM/NOD) histogenetic types. These include (1) the relationship of moles to melanoma of the SSM/ NOD types not found in melanoma arising in lentigo maligna (LMM), desmoplastic neurotrophic melanoma (DNM), mucosal lentiginous melanoma (MLM), or acral lentiginous melanoma (ALM); (2) the strong sunlight association in lentigo maligna (LM) and LMM not always present in SSM/NOD and not likely at all in acral or mucosal lesions (ALM, MLM); (3) epidemiological differences of age, race, and prognosis among the various subtypes; and (4) analogies to neoplasms in other organ systems. These data justify the following conclusions: (1) Variants of melanoma exist as in other neoplasms. (2) They are of epidemiological and therapeutic importance. (3) Until further data are available or networked, data base analysis should use microstage measurements in the common forms of SSM and NOD only, and approach the unusual variants separately and cautiously.

The multidisciplinary melanoma center.

The evolution of the multidisciplinary melanoma clinics from 1965 to the present is reviewed. The University of California Melanoma Center database is presented as a model of actual visualization of the data in the care of individual melanoma patients. The basis of the ideal melanoma multidisciplinary center is given with common attributes that could be shared among all clinics, thus establishing a national network of such clinics.

Cutaneous melanoma in women: anatomic distribution in relation to sun exposure and phenotype.

An analysis of the relationship between the anatomic site of cutaneous melanoma, sun exposure, and phenotype was conducted in 355 women with histologically confirmed superficial-spreading melanoma and in 935 control subjects. The most frequent site for superficial-spreading melanoma was the leg. However, when major sun-related and phenotype risk factors were examined by site, risk ratios were lowest for melanomas that occurred on the leg. A history of frequent sunburns during elementary or high school, increased number of self-assessed large nevi, and blond hair were more strongly associated with melanoma sites other than the leg. Tumors on the trunk were more likely than tumors at other sites to be associated with histological evidence of a preexisting nevus. Results of this work indicate that associations between melanoma phenotypic factors may differ by anatomic site.

Nevus counting as a risk factor for melanoma: comparison of self-count with count by physician.

BACKGROUND: The number of total body nevi is a major risk marker for malignant melanoma. No previous study has evaluated the accuracy of whole body large nevus (> or = 5 mm) self-counts. OBJECTIVE: Our purpose was to evaluate the accuracy of large nevus self-counts by sex, age, educational level, body site, family history of skin cancer, and nevus characteristics. METHODS: Self-counting of large nevi by 125 patients was compared with physician counting, with attention to nevus characteristics. RESULTS: Overall, 79% of the self-counts agreed to within +/- 3 nevi of the physician's count. Analysis of variance revealed that the presence of nonpigmented or flat nevi significantly increased the chance of subject undercount, as did male sex. CONCLUSION: Self-counts of large nevi are comparable to physician's counts and may be useful for melanoma screening.

Inter-observer variability among pathologists' evaluation of malignant melanoma: effects upon an analytic study.

This study examined whether inter-observer variability in rating tumor characteristics affected results of an investigation of surveillance bias and malignant melanoma at the Lawrence Livermore National Laboratory. The 20 cases from the Laboratory and their 36 non-Laboratory controls belonged to the same pre-paid health plan and were diagnosed with melanoma between 1970 and 1984. Tumors were independently and then jointly rated by three dermatopathologists blind to the subjects' Laboratory status. The mean difference between the reviewers and the consensus reading for tumor thickness was small, ranging from -0.06 mm (95% confidence interval [CI]--0.12, 0.00) to 0.00 mm (95% CI--0.07, 0.07). Agreement was much lower for histologic type (kappa = 0.48, 95% CI 0.37, 0.58). Because the inter-observer variability, the study's hypothesis was rejected by analyses based on data from the consensus reading and two reviewers, but not on data from the third reviewer. These findings suggest that epidemiologists using data subject to inter-observer variability may want to employ consensus instead of individual ratings.

Risk factors for melanoma incidence in prospective follow-up. The importance of atypical (dysplastic) nevi.

BACKGROUND AND DESIGN: Assessment of melanoma risk factors can help identify individuals at greatest risk for melanoma. Previous studies were retrospective case-control or prospective without control groups. A prospective group of 3889 employees without previous melanoma or family history of multiple melanoma at the Lawrence Livermore (Calif) National Laboratory were examined as part of a melanoma screening program. Their subsequent incidence of melanoma in relationship to potential melanoma risk factors, which were recorded at the first examination, was determined. RESULTS: Nine invasive melanomas developed after initial examination among the studied population over an 8-year period with an average follow-up of 5 years. The presence of an easily recognized pattern of definite clinically atypical (dysplastic) nevi was present in 7% of employees and was associated with a cumulative melanoma risk of 1.9%. It was the strongest risk factor, with a relative risk of 47 compared with the 0.04% cumulative melanoma risk in the 64% of employees with no atypical (dysplastic) moles (chi 2 for equal risk, P = 7 x 10(-8). Significant, but less marked associations with melanoma risk were found for the total number of moles and for a history of many moles in other family members, with a maximal relative risk of 11.6 and 10.4, respectively. CONCLUSION: A small subgroup of the population with easily recognizable definite atypical (dysplastic) nevi have a marked increased risk of melanoma. Smaller significant melanoma risks were found for a total number of moles and a family history of many moles.

A multiobserver, population-based analysis of histologic dysplasia in melanocytic nevi.

BACKGROUND: Nevi that are clinically atypical and histologically dysplastic have been associated with increased melanoma risk. There are few reproducibility studies or population-based studies of nevus histology. OBJECTIVE: Our purpose was to quantify concordance in histologic diagnosis of melanocytic lesions among a diverse group of pathologists, to assess intraobserver concordance by comparing readings of the same slide as well as of adjacent recuts from the same block, to correlate histology with nevus appearance and melanoma risk, and to estimate the range of prevalence of histologic dysplasia. METHODS: Histologic slides were prepared from 149 tissue blocks of pigmented lesions from melanoma cases, relatives, and controls. Six dermatopathologists independently evaluated the lesions for histologic dysplasia, without prior agreement on criteria. RESULTS: According to kappa statistics, intraobserver reproducibility was substantial, and interobserver concordance was fair, despite differences in criteria. The estimated prevalences of histologic dysplasia for the six pathologists ranged from 7% to 32%. Histologic dysplasia was correlated with nevus size for most observers, confounding the observed correlation between nevus appearance and histology. CONCLUSION: Although experienced dermatopathologists use different diagnostic criteria for histologic dysplasia, their usage is consistent. Histologic changes ascribed to melanocytic dysplasia are prevalent in the white population for all pathologists. The term nevus with histologic dysplasia should be used in preference to dysplastic nevus.

Melanoma risk factors and atypical moles.

Despite important advances in the treatment of melanoma, the prognosis for advanced disease remains discouraging. This fact, in combination with a worldwide epidemic of melanoma among persons of white skin type, has focused attention on identifying melanoma in its early, surgically curable stages. Attention has also been directed toward pinpointing which persons are at increased risk for melanoma to reduce risk where possible and to aid early diagnosis. Essentially all epidemiologic studies have identified an increased number of melanocytic nevi as an important risk factor in the development of melanoma, but controversy has arisen concerning the risk associated with certain types of nevi, particularly "dysplastic" nevi. We review melanoma risk factors and examine the relationship between melanocytic nevi and melanoma to clarify for primary care physicians what is "known" (non-controversial) and what is "unknown" (controversial). We propose a working definition of an atypical mole phenotype and outline an approach to managing high-risk patients.

The pathology of melanoma as a basis for prognostic models: the UCSF experience.

A patient survival model is proposed which allows visualization of a data base, and which includes only routine and commonly recorded attributes in most melanoma clinics. It is proposed that a network of such data be collected for meta-analysis (MELNET), which could make stratification within the individual subsets more significant by virtue of the large numbers. Such a network could then be fully tested in various melanoma clinics for clinical usefulness.

Pigmented lesion pathology: the specimen and its report. A personal and probably biased approach.

The author outlines general principles and pitfalls in the pathologic interpretation of pigmented skin lesions, then focuses on issues related specifically to gross tissue specimens and to the histologic report. He concludes that definitive therapy for melanoma should not be based on partial biopsies, that frozen sections are not indicated, and that the pathologist should report all of the relevant histologic attributes whenever possible.