An evidence-based staging system for cutaneous melanoma

A completely revised staging system for cutaneous melanoma was implemented in 2003. The changes were validated with a prognostic factors analysis involving 17,600 melanoma patients from prospective databases. This major collaborative study of predicting melanoma outcome was conducted specifically for this project, and the results were used to finalize the criteria for this evidence-based staging system. In fact, this was the largest prognostic factors analysis of prospectively followed melanoma patients ever conducted. Important results that shaped the staging criteria involved both the tumor-node-metastasis (TNM) criteria and stage grouping for all four stages of melanoma. Major changes in the staging include: (1) melanoma thickness and ulceration are the dominant predictors of survival in patients with localized melanoma (Stages I and II); deeper level of invasion (ie, IV and V) was independently associated with reduced survival only in patients with thin or T1 melanomas. (2) The number of metastatic lymph nodes and the tumor burden were the most dominant predictors of survival in patients with Stage III melanoma; patients with metastatic nodes detected by palpation had a shorter survival compared with patients whose nodal metastases were first detected by sentinel node excision of clinically occult or "microscopic" metastases. (3) The site of distant metastases (nonvisceral versus lung versus all other visceral metastatic sites) and the presence of elevated serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in patients with Stage IV or distant metastases. (4) An upstaging was implemented for all patients with Stage I, II, and III disease when a primary melanoma is ulcerated by histopathological criteria. (5) Satellite metastases around a primary melanoma and in-transit metastases were merged into a single staging entity that is grouped into Stage III disease. (6) A new convention was implemented for defining clinical and pathological staging so as to take into account the new staging information gained from lymphatic mapping and sentinel node biopsy.     

Melanoma of unknown primary origin: A population-based study in the Netherlands

AimFew population-based studies have been published on melanoma of unknown primary origin (MUP). This study’s aim is to describe characteristics and survival of MUP patients in the Netherlands, based on nationwide data from the Netherlands Cancer Registry (NCR).MethodsPatient and tumour characteristics of MUP patients were retrieved from the NCR. Subgroups were made according to metastatic site: nodal or distant. Survival rates were calculated using the Kaplan–Meier method. To obtain a better insight in the composition and prognosis of the MUP group, the survival was compared to that of patients with melanoma of a known primary origin (MKP), tumour-node-metastasis (TNM) stage III and IV.ResultsOf all 33,181 melanoma patients diagnosed between 2003 and 2009, 2.6% (n = 857) were diagnosed with MUP. MUP patients with nodal metastases had a similar survival as MKP stage III with macroscopic nodal involvement. After stratification according to the number of involved lymph nodes, the survival of patients with nodal metastases with one involved lymph node was not significantly different between MUP and MKP. The survival of MUP patients with two or more involved lymph nodes was slightly worse than that of MKP stage III patients with macroscopic nodal involvement with two or more involved lymph nodes. MUP patients with distant metastases had a similar survival as MKP stage IV. After stratification according to number of metastatic sites and metastatic site category, the survival in MKP stage IV patients with (sub)cutaneous metastases was slightly worse than MUP distant patients with (sub)cutaneous metastases.ConclusionsThe results of this study imply that MUP patients form a heterogeneous group, and that MUP patients with nodal metastases could be classified as stage III melanoma with macroscopic nodal involvement, and MUP patients with distant metastases as stage IV melanoma.     

Role of sentinel lymphadenectomy in thin invasive cutaneous melanomas.

PURPOSE: Regional lymph node status is the strongest prognostic determinant in early-stage melanoma. Lymphatic mapping and sentinel lymphadenectomy (LM/SL) is standard to stage regional nodes because it is accurate and minimally morbid, yet its role for thin (相似文献   

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.     

Melanoma of the head and neck

Opinion statement Staging of cutaneous melanoma has changed in recent years with an increased emphasis upon thickness and ulceration on prognosis of early stage disease. Cutaneous melanoma of the head and neck is treated with complete surgical resection in early stage disease. Resection margins are determined by the size, depth, and presence of satellite lesions. Evaluation for regional and distant metastatic disease is necessary in all cases of advanced stage disease. Sentinel lymph node biopsy and possible parotidectomy and neck dissection should be considered in head and neck cutaneous melanomas greater than 1 mm in thickness or with ulceration. Adjuvant therapy may be indicated in advanced primary, nodal, and metastatic disease. Mucosal melanoma of the head and neck remains a difficult disease to treat, with high locoregional recurrence rates and poor prognosis despite aggressive therapy.     

Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.     

The revised American Joint Committee on Cancer staging system for melanoma

Substantial progress has been made in identifying the most significant clinical and pathologic characteristics of melanoma that predict for metastasis and survival. The American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma was recently revised to include these prognostic variables. Major changes in the staging include: (1) melanoma thickness and ulceration but not level of invasion will be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, "microscopic") versus clinically apparent (ie, "macroscopic") nodal metastases will be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactate dehydrogenase (LDH) will be used in the M category; (4) all patients with stage I, II, or III disease will be upstaged when a primary melanoma is ulcerated; (5) satellite metastases around a primary melanoma and in-transit metastases will be merged into a single staging entity that is grouped into stage III disease; and (6) distinct definitions for clinical and pathologic staging will take into account the new staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.     

Tumorigenicity and dissemination of primary and metastatic human melanomas implanted into different sites in athymic nude mice

In the present study, the growth features and metastatic capacity of human primary and metastatic melanomas transplanted by different routes in nude mice was examined. Eight different human melanoma early cell cultures derived from 3 primary tumors, 1 local recurrence and 4 metastatic lesions of 6 melanoma patients were characterized for cell surface HLA (class I and II) and melanoma-associated antigens and karyotype. These tumors were then transplanted in CD-1 outbred nude mice by subcutaneous, intraperitoneal and intrasplenic routes. It was found that 7 out of 8 melanomas were tumorigenic after subcutaneous implantation without giving rise to metastases; 5 out of 7 melanomas grew when injected intraperitoneally and 3 of them disseminated to peritoneal organs and infiltrated intraperitoneal lymph nodes, liver and pancreas; of 8 melanomas implanted intrasplenically 4 grew in the spleen or invaded intraperitoneal lymph nodes, liver, pancreas, ovaries or lungs. Primary and metastatic melanomas did not differ in the pattern of dissemination. In fact, 2 out of 4 metastases and 1 of 3 primary tumors and 1 recurrence disseminated after intrasplenic or intraperitoneal inoculation. Heterogeneity in the growth pattern of different metastases of the same melanoma patient was also found. No correlation could be detected between the metastatic ability of melanoma cells studied and clinical stage of patients, tumor cell karyotype abnormalities, modal number or with the antigenic phenotype.     

A multifactorial analysis of melanoma. IV. Prognostic factors in 200 melanoma patients with distant metastases (stage III)

A multifactorial analysis of 200 cutaneous melanoma patients with distant metastasis (stage III) was performed on 13 clinical and pathological factors using the Cox regression analysis. There were only three dominant prognostic variables that independently predicted the patient's clinical course: (1) number of metastatic sites (1 vs. 2 vs. greater than or equal to 3, p less than 0.00001), (2) remission duration (less than 12 mo vs. greater than or equal to 12 mo, p = 0.0186), and (3) the location of the metastases (visceral vs. nonvisceral vs. combined, p = 0.0192). Factors that were not significant in the multifactorial analysis included the patients' age and sex, the site of the primary melanoma, the sequence of metastases, and all histopathological features of the primary melanoma (thickness, level of invasion, ulceration, growth pattern, pigmentation, and lymphocyte infiltration). For a single metastatic site, the 1-yr survival rate was 36%, while it was only 13% for 2 sites, and 0% for greater than or equal to 3 sites (p less than 0.00001). The 1-yr survival for patients was 40% for nonvisceral sites (skin, subcutaneous, distant lymph nodes) compared to only 11% for visceral metastases and 8% for combined sites (p less than 0.00001). Pulmonary metastases were associated with a significantly higher survival rate than metastatic melanoma in any other visceral site. The most common first site of distant metastases (either alone or in combination) was skin (38%), lung (36%), liver (20%), and brain (20%). The skin, subcutaneous and distant lymph node group was the first site of metastases in 59% of patients. This finding emphasizes the importance of careful physical exams in routine metastatic evaluations. Only a minority (25%) of stage I patients progressed to stage III disease after a median interval of 2.8 years. In contrast, the majority (75%) of melanoma patients with nodal metastases (stage II) progressed to stage III disease after a median duration of only 11 mo. Of the patients who eventually developed stage III disease, 95% of those who initially presented with stage II disease progressed within 3 yr, while stage I patients who progressed to stage III did not reach a 95% cumulative incidence until 8 yr.     

CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease.

PURPOSE: The cell adhesion molecule CEACAM1 is involved in intercellular adhesion and subsequent signal transduction events in a number of epithelia. CEACAM1 downregulation has been demonstrated in colorectal and prostate carcinomas. This study sought to analyze whether its expression in malignant melanoma is associated with metastasis. PATIENTS AND METHODS: CEACAM1 expression was immunohistochemically evaluated in 100 primary cutaneous malignant melanomas and correlated with metastasis in a 10-year follow-up. Furthermore, CEACAM1 expression was analyzed in metastatic lesions (11 distant metastases and six sentinel lymph node metastases). Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard regression analysis adjusted for standard prognostic indicators were performed to assess the prognostic relevance of CEACAM1 expression. RESULTS: A total of 28 of 40 patients with CEACAM1-positive primary melanomas developed metastatic disease, compared with only six of 60 patients with CEACAM1-negative melanomas. Often, the strongest CEACAM1 expression was observed at the invading front. In addition, CEACAM1 expression was preserved in the metastatic lesions. Kaplan-Meier analysis revealed a highly significant association between CEACAM1 expression and metastasis (P <.0001); multivariate Cox regression analysis, including CEACAM1 expression status adjusted for tumor thickness, presence of ulceration, and mitotic rate, confirmed that CEACAM1 is an independent factor for the risk of metastasis and demonstrated that the predictive value of CEACAM1 expression is superior to that of tumor thickness. CONCLUSION: Expression of the cell adhesion molecule CEACAM1 in the primary tumors in melanoma patients is associated with the subsequent development of metastatic disease. This raises the possibility of a functional role for this cell adhesion molecule in the metastatic spread it indicates.     

Long-term prognostic significance of HSP-70, c-myc and HLA-DR expression in patients with malignant melanoma.

AIM: Use of molecular markers indicative of the tumour oncogenic potential and host response may enhance our prognostic information for more effective treatment of melanoma patients. The roles of HSP-70 protein, c-myc oncogene and HLA-DR antigen expression were examined in melanoma patients and related to prognostic factors, recurrence rate and long-term survival. METHODS: Forty patients with tumours thicker than 1 mm were included in this study. All had elective node dissection and were followed for at least 7 years. Twenty-two had microscopic nodal metastases. Both primary melanoma tumour and lymph nodes were examined for the immunohistochemical expression of HSP-70 protein, c-myc oncogene and HLA-DR antigen. RESULTS: Eighteen patients had a recurrence (45%) and 23 patients survived overall (57.50%). Positive HSP-70 expression was observed in 52.50% of the primary melanomas and was associated with improved overall survival, especially in the patient group with tumours > or = 1.5 mm (70%vs 26.70%, P=0.0159). C-myc oncogene was overexpressed in 47.50% and HLA-DR antigen in 42.50% of the primary melanomas, but no correlation with survival was observed. The expression profile of these molecular markers in the primary tumour did not predict the status of regional nodes. HLA-DR expression in lymph nodes was observed exclusively in the nodal tissue surrounding the metastatic melanoma tumour in five patients. CONCLUSIONS: The immunohistochemical expression profile of HSP-70 but not of c-myc oncogene or HLA-DR antigen in the primary melanoma tumour could be of certain value in the identification of patients with graver prognosis who may benefit from more aggressive therapeutic strategies. Copyright Harcourt Publishers Limited.     

Management of nodal metastases from head and neck melanoma

Ninety-three patients with nodal metastases from melanoma (stage II) located in the head and neck underwent surgery at the National Cancer Institute of Milan. Different surgical techniques were employed, ranging from radical to conservative treatment. Analysis of the data shows no significant difference from an oncological standpoint between radical and conservative surgery when a radical dissection is performed. Elective nodal dissections for malignant melanoma of the head and neck region, like those at other sites of lymphatic drainage such as the groin and axilla, did not prove beneficial. We do recommend parotidectomy in cases where the primary tumor arises in the superior area of the head. The number of nodes involved and the type of disease spread constitute the major prognostic factors, as in the case of melanomas located in other sites. Our data further indicate that the incidence of distant and local recurrence is not influenced by the type of dissection performed.     

Comparison between lentigo maligna melanoma and other histogenetic types of malignant melanoma of the head and neck. Scottish Melanoma Group.

A study of 953 invasive cutaneous malignant melanomas of the head and neck was performed to determine differences between lentigo maligna melanoma and other histogenetic types with regard to patients and sites affected; prognosis was analysed in 595 of these cases. The cases studied comprised all head and neck melanomas registered with the Scottish Melanoma Group between 1979 and 1992, apart from the 3% of cases that were unclassifiable or rare histogenetic types. The histogenetic types of melanoma were 498 (52%) lentigo maligna melanoma (LMM), 237 (25%) superficial spreading melanoma (SSM) and 218 (23%) nodular melanoma (NM). All types increased in incidence throughout the study period. Patients with LMM (mean age 73 years) and NM (mean 68 years) were significantly older than those with SSM (mean 57 years). There were significant anatomical subsite differences related to sex of patients and histogenetic type of melanoma; melanomas on the face were more frequent in females and 90% of LMM occurred at this site, whereas melanomas on the scalp, neck and ears were more frequent in men. Kaplan-Meier estimates of the probability of survival were produced for the 595 of these 953 patients with 5 year follow-up details. In this group of patients the prognostic significance of tumour thickness, Clark level of invasion, ulceration, histogenetic type of melanoma and number of mitoses were studied using stepwise variable selection of procedures. Each of these possible prognostic factors attained individual significance but the tumour thickness was the dominant risk factor in the proportional hazards analysis. When patients were divided into four sex/ulceration subgroups (male/ulcerated, female/ulcerated, male/non-ulcerated, female/non-ulcerated) and analysed by proportional hazards analysis, no variable other than the tumour thickness had any further prognostic effect. Histogenetic type did not remain an independent prognostic variable at this stage. Despite sex and subsite differences, the prognosis for invasive lentigo maligna melanoma does not differ from that for other histogenetic types after controlling for tumour thickness.     

The natural history and patterns of metastases from mucosal melanoma: an analysis of 706 prospectively-followed patients

BackgroundWe examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would differ from primary mucosal melanomas at different anatomical sites.Patients and methodsClinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites.ResultsThe anatomic sites of the primary mucosal melanomas were from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%), and other sites (3.0%). At initial diagnosis, 14.5% were stage I disease, 41% Stage II, 21.5% Stage III, and 23.0% stage IV. Predominant metastatic sites were regional lymph nodes (21.5%), lung (21%), liver (18.5%), and distant nodes (9%). Oral cavity mucosal melanoma had a higher incidence of regional nodal metastases (31.7% versus 19.8%,P = 0.009), and a higher incidence of lung metastases (32.5% versus 18.5%,P = 0.007) compared to other primary mucosal melanomas. There was a 10% incidence of CKIT mutation and 12% BRAF mutation. Mucosal melanomas from nasal pharyngeal and oral, gastrointestinal, gynecological, and urological had a similar survival with a 1-year survival rate (88%, 83%, 86%), 2-year survival rate (66%, 57%, 61%), 5-year survival rate (27%, 16%, 20%), respectively.ConclusionsThe largest sample size allows, for the first time, a comparison of primary melanoma stage and patterns of metastases across anatomical sites. With few exceptions, the presenting stages, incidence of nodal and distant metastases, the site of predilection of distant metastases, or overall survival were similar despite different primary anatomic sites. These findings suggest that clinical trials involving mucosal melanomas and the administration of systemic therapy can be applied equally to mucosal melanomas regardless of their primary anatomic site.     

BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma

BRAF oncogenic mutations have been identified in significant numbers of melanocytic lesions. To correlate BRAF mutation and melanoma progression, we screened BRAF mutations in 65 melanocytic lesions, including nevi, radial growth phase (RGP), vertical growth phase (VGP) melanomas, and melanoma metastases, as well as 25 melanoma cell lines. PCR and direct sequencing were used to analyze DNA samples extracted from laser capture microdissected tissues. A similar high frequency (62-72%) of BRAF oncogenic mutations was identified in melanocytic nevi, VGP, metastatic melanomas, and melanoma cell lines [H. Davies et al., Nature (Lond.), 417: 949-954, 2002; P. M. Pollock et al., Nat. Genet., 33: 19-20, 2002; and M. S. Brose et al., Cancer Res., 62: 6997-7000, 2002]. In striking contrast, we found BRAF lesions in only 10% of the earliest stage or RGP melanomas. These findings imply that BRAF mutations cannot be involved in the initiation of the great majority of melanomas but instead reflect a progression event with important prognostic implications in the transition from the great majority of RGP melanomas to VGP and/or metastatic melanoma.     

Prognostic factors in head and neck melanoma. Effect of lesion location

Cutaneous malignant melanomas of the head and neck are prognostically engimatic. In addition to known prognostic determinants of stage and lesion microstage, lesion location also appears to have prognostic importance. The authors have reviewed a series of 83 microstaged head and neck melanoma patients in order to analyze the relative importance of these factors. There were 36 males and 47 females with a median age of 56 years. Eighty-one percent had pathologic Stage I disease, 7% were Stage II, and 12% were Stage III. The primary location was face in 32 patients, neck in 18, ear in 12, and scalp in 21 patients. The actuarial 5-year survival according to lesion thickness was 86% for melanoma less than 1.0 mm, 56% for 1 to 2 mm thick lesions, 47% for 2.1 to 4 mm thick lesions, and 25% for melanomas greater than 4.0 mm. The 5-year survival according to lesion location was 78% for facial and 58% for neck melanomas; for ear and scalp, the respective survivals were 33% and 37%. Median thickness was 2.0 mm for facial and 1.85 mm for neck lesions. It was 2.7 mm for ear and 2.0 mm for scalp lesions (differences not significant). There were no microstage factors that correlated with the adverse prognosis seen with scalp and ear melanomas. Multivariate analysis in the entire series (all clinical stages) showed the following to be significant: stage, thickness, and location of the primary melanoma (all less than 0.0002). In clinical Stage I melanoma, the significant prognostic factors were location (P = 0.035), thickness (P = 0.008), level (P = 0.024), and ulceration (P = 0.035). The prognosis of head and neck melanoma is uniquely influenced by location of the primary lesions in addition to stage, thickness, level, and ulceration, as observed with other cutaneous melanomas at other sites. Ear and scalp melanomas are high-risk lesions whose poor prognosis is not readily explained by any of the microstage factors reviewed.     

Survivin expression by metastatic melanoma predicts poor disease outcome in patients receiving adjuvant polyvalent vaccine

Survivin and livin are members of the inhibitor of apoptosis protein (IAP) family. We hypothesized that elevated expression levels of these 2 IAP genes in resected advanced-stage metastatic melanoma lesions would be associated with poor disease outcome in patients receiving a polyvalent therapeutic cancer vaccine (Canvaxintrade mark). A quantitative real-time RT-PCR (qRT) assay for survivin and livin genes was used to assess mRNA expression in 63 metastatic melanomas obtained during cytoreductive surgery of American Joint Committee on Cancer (AJCC) stage IV melanoma. Nineteen of 63 metastatic melanoma patients received Canvaxin pre- and postoperatively, and 37 patients received only postoperative Canvaxin. Expression of survivin and livin protein was assessed by immunohistochemistry (IHC) and then correlated with mRNA. Survivin mRNA was detected in 62 of 63 (98%) melanoma specimens ranging from 0-5.96 x 10(4) mRNA copies of total RNA. Lower mRNA copy levels of survivin significantly correlated with improved overall survival among the 37 patients who received Canvaxin postoperatively but not preoperatively (log-rank test, p = 0.023). Among patients with low survivin mRNA copies, those who received postoperative Canvaxin did significantly better than patients who received pre- and postoperative Canvaxin (p = 0.003). Livin mRNA was detectable in 60 of 63 (95%) metastatic melanoma specimens but had no significant prognostic utility. These studies demonstrate that lower levels of survivin in recurrent metastatic melanomas are associated with significantly improved survival in patients receiving postoperative adjuvant immunotherapy. Overall, the study indicates survivin expression in metastatic melanomas can significantly influence disease outcome and patient responses to immunotherapy.     

A new American Joint Committee on Cancer staging system for cutaneous melanoma

The Melanoma Staging Committee of the AJCC has proposed major revisions of the melanoma TNM and stage grouping criteria. The committee members represent most of the major cooperative groups and cancer centers worldwide with a special interest in melanoma; the committee also collectively has had clinical experience with over 40,000 patients. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include 1) melanoma thickness and ulceration, but not level of invasion, to be used in the T classification; 2) the number of metastatic lymph nodes, rather than their gross dimensions, the delineation of microscopic versus macroscopic lymph node metastases, and presence of ulceration of the primary melanoma to be used in the N classification; 3) the site of distant metastases and the presence of elevated serum LDH, to be used in the M classification; 4) an upstaging of all patients with Stage I,II, and III disease when a primary melanoma is ulcerated; 5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into Stage III disease; and 6) a new convention for defining clinical and pathologic staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel lymph node biopsy. The AJC Melanoma Staging Committee invites comments and suggestions regarding this proposed staging system before a final recommendation is made.     

Progressive increase in telomerase activity from benign melanocytic conditions to malignant melanoma

The expression of telomerase activity and the in situ localization of the human telomerase RNA component (hTR) in melanocytic skin lesions was evaluated in specimens from sixty-three patients. Specimens of melanocytic nevi, primary melanomas and subcutaneous metastases of melanoma were obtained from fifty-eight patients, whereas metastasized lymph nodes were obtained from five patients. Telomerase activity was determined in these specimens by using a Polymerase Chain Reaction-based assay (TRAP). High relative mean telomerase activity levels were detected in metastatic melanoma (subcutaneous metastases = 54.5, lymph node metastases = 56.5). Much lower levels were detected in primary melanomas, which increased with advancing levels of tumor cell penetration (Clark II = 0.02, Clark III = 1.1, and Clark IV = 1.9). Twenty-six formalin-fixed, paraffin-embedded melanocytic lesions were sectioned and analyzed for telomerase RNA with a radioactive in situ hybridization assay. In situ hybridization studies with a probe to the template RNA component of telomerase confirmed that expression was almost exclusively confined to tumor cells and not infiltrating lymphocytes. These results indicate that levels of telomerase activity and telomerase RNA in melanocytic lesions correlate well with clinical stage and could potentially assist in the diagnosis of borderline lesions.     

Prognosis of level V malignant melanoma

Level V melanomas have been reported to have a poor prognosis, but in-depth analyses of prognostic factors and treatment have not been reported. From 1952 through 1982, 41 patients presented with primary Clark's Level V melanomas. There were 23 patients who presented with clinical Stage I disease and 18 with Stage II. Among Stage I patients, 9 were treated by wide excision alone and 13 underwent wide excision plus prophylactic regional lymph node dissection (RLND); 8 of 13 patients had histologically positive nodes. Twelve Stage II patients were treated by wide excision and RLND (including three hemipelvectomies), and four refused surgery. The 5-year survival was 52%. For Stage I patients, survival was 62% and disease-free survival (DFS) 28% at 5 years; 6 of 10 recurrences were local or regional only. Prophylactic RLND reduced the incidence of recurrence but did not appear to influence survival rates. Among 14 evaluable Stage II patients, overall survival was 60% and DFS 42% at 3 years; of 4 patients who subsequently had a recurrence, 3 had distant metastases. All seven patients with distant metastases at the time of first recurrence died of disease within 14 months (median, 4 months) of detection of metastatic disease. Primary melanomas of the foot (11 patients) and trunk (4 patients) appeared to have a worse prognosis than other sites. Ulceration (seen in 21 patients) did not appear to significantly influence outcome. These data suggest that most patients with Level V melanoma present with clinically localized disease. Prophylactic RLND did not significantly affect overall survival. The invasiveness of these deep tumors appears to reduce the influence of other factors, including primary site, sex, race, and ulceration. The prognosis of patients with Level V melanoma, even with clinically or histologically positive lymph nodes, is not hopeless, and these patients should be treated aggressively.