Staging Of Cutaneous Melanoma Research Articles

Pathobiology of the sentinel node

Lymphatic mapping and sentinel lymph node biopsy have been established as definitive procedures for the staging of cutaneous melanoma. Large-scale studies that have been recently conducted and that are ongoing suggest a therapeutic role for lymphatic mapping/sentinel node biopsy in the management and prognosis of melanoma patients with early lymph node metastases. Sentinel node biopsy has been shown to extend disease free survival and increase melanoma-specific survival for patients with early nodal metastases according to interim analysis of the Multicenter Selective Lymphadenectomy Trial 1 (MSLT-1). The proper evaluation of sentinel lymph nodes requires histologic and immunohistochemical analysis of multiple levels. Immune modulation has been shown to play an important role in nodal metastasis. There is increasing evidence for the efficacy of lymphatic mapping and sentinel lymph node biopsy in predicting prognosis, reducing the morbidity traditionally associated with regional lymph node dissection and increasing survival in subgroups of patients with cutaneous melanoma. Further study is needed to determine the role of the immune system in the spread of nodal metastases and the role of immunomodulatory therapy to prevent or possibly even reverse nodal metastases.

Multimarker real‐time reverse transcription‐PCR for quantitative detection of melanoma‐associated antigens: a novel possible staging method

Detection of melanoma cells in peripheral blood is a promising method for monitoring haematogenous spread of melanoma cells. It enables us to detect early metastasis and to better stratify candidates for adjuvant immunotherapy. Inconsistent data on the sensitivity and clinical relevance of this method have been reported. We developed a multimarker real-time reverse transcription-PCR (RT-PCR) for quantification of five melanoma markers: Melan-A, gp100, MAGE-3, MIA and tyrosinase. In this prospective study, 65 patients with resected cutaneous melanoma stage IIB-III were screened. Peripheral blood samples were collected every 3 months for the following 18 months, and circulating melanoma cells were examined and compared with clinical staging results. Eighteen patients relapsed during the trial and showed different types of melanoma progression. All these patients experienced statistically significant tumour marker elevation in the period from 0 to 9 months before the disease progression. MAGE-3 was the most sensitive progression marker. In patients with progression, we observed three concordant positive markers in 39% of cases, two concordant positive markers in 28%, and finally one marker in 33%. This report describes a multiple-marker real-time RT-PCR, which is able to provide quantitative data on melanoma markers in the peripheral blood of melanoma patients. Measurement of the studied molecular markers in our hands represents a prognostic factor and a useful method for early detection of metastasis and treatment response of melanoma patients.

Comparison Among Clark's, Breslow's, and TNM Classifications for Cutaneous Head and Neck Malignant Melanoma

This retrospective study was carried out to assess the prognostic value of three classification systems used for staging cutaneous head and neck malignant melanoma (CHNME). Fifty-three patients with histologically proven CHNME were analyzed. Thirty patients were never treated before admission, whereas 23 (43.4%) had a second radical resection of the primary tumor location, 9 (17%) had neck nodes, none had distant metastasis, and all had a minimum of 5 years of follow-up. Results show that T-stage is the most important clinical prognostic parameter, whereas Clark's and Breslow's classifications have lower impact in defining prognosis. Sites of primary tumor determines different clinical outcomes, but this does not reach statistically significant values. A second surgery on the primary tumor location is possible and is effective toward survival. No statistical differences were noted between the previously untreated and treated groups. Neck nodes have to be removed with neck dissection, and this regimen can improve the clinical outcome; however, only 40% of neck positive patients survive more than 5 years.

A simplified staging system in cutaneous melanoma to select patients for adjuvant trials

19003 Background: Most clinical trials with adjuvant therapy in melanoma concentrate on high-risk patients including those with metastases to regional lymph nodes (LN), stage III and locally advanced T4, i.e., stage IIB and IIC. These trials may be missing the advantageous results in the relatively earlier stages. Methods: We reviewed the new American Joint Committee on Cancer (AJCC) for cancer staging of cutaneous melanoma and Balchs’ data for the prognostic factors. The data was correlated to patients’ survival expressed by the natural history of the disease. Results: We grouped the reported survival data into 3 risk groups, excluding patients with distant metastases. Group 1: 2–4mm deep primary with ulceration, >4mm deep primary without ulceration, micrometastases to 1–3 LN, primary not ulcerated; Group 2: >4mm deep primary with ulceration, micrometastases to 1–3 LN ulcerated primary, macrometastases to 1–3 LN, primary not ulcerated intransit metastases/satellitosis, without LN metastases; Group 3: macrometastases to 1–3 LN, ulcerated primary, metastases to 4 or more LN, matted LN, and/or intransit, metastases/satellitosis with LN metastases. The table summarizes the results. Conclusions: 1. Over one-third of the patients in group 1 died of disease in the first 5 years. They should be considered at intermediate risk and should receive adjuvant therapy. 2. Patient prognosis should determine the intensity of target therapy utilized in the adjuvant arena. While anti-CTLA-4 may be sufficient for group 1, the addition of anti-kinases may be required in group 2 and more so in group 3. [Table: see text] No significant financial relationships to disclose.

Does deprivation of area of residence influence the incidence, tumour site or T stage of cutaneous malignant melanoma? A population-based and clinical database study

This study aimed to document the incidence of malignant melanoma at specific subsites in men and women, stratified by deprivation of area of residence in southeast England, and to explore the association between deprivation and tumour thickness at diagnosis. Data were extracted on 6468 cases from the Thames Cancer Registry for the years 1998 to 2002, and data on, and 508 cases were extracted from the clinical database of the Skin Tumour Unit, St Thomas' Hospital, for the years 1996 to 2004. The postcode of residence was used to assign quintiles of deprivation based on the income domain stated in the Indices of Deprivation 2000. For both males and females, the incidence was higher for those living in the most affluent areas. The trunk was the most common site in males and the lower limbs in females. All sites showed an affluence gradient, although this was least pronounced for head and neck tumours. Distribution of T stage at diagnosis did not differ by deprivation of area of residence.

Natural Killer Receptors on CD8 T Cells and Natural Killer Cells from Different HLA-C Phenotypes in Melanoma Patients

Because immune mechanisms involved in cutaneous melanoma have not been fully elucidated, efforts have been made to achieve prognosis markers and potential targets for immune therapies, but they have not been entirely fruitful thus far. Therefore, the goal of this study was to investigate the involvement of early changes in CD8 T cells and CD56 natural killer (NK) cells expressing NK receptors in different HLA-C dimorphism groups of melanoma patients. CD8 T cells and CD56 NK cells were analyzed in 41 patients and 39 sex- and age-matched controls with different HLA-C genotypes by flow cytometry. HLA-C dimorphism at position 80 was tested by PCR sequence-specific primers and PCR sequence-specific oligonucleotide to examine whether it could mediate in the emergence of cells expressing killer cell immunoglobulin-like receptors. Thirty-five of 41 patients had benign sentinel node, and showed an imbalance in the absolute number of CD8(+)DR(+) or CD8(+)CD161(+) peripheral blood T cells according to the CD28 coexpression compared with controls. CD8(+)CD28(-)CD158a(+) T and CD56(+)CD158a(+) NK cells were significantly increased in HLA-C(Lys80) homozygous nonmetastatic patients, whereas only CD56(+)CD158a(+) NK cells increased in heterozygous ones. An up-regulation of the CD158a KIR receptor was also seen on NK cells but not in T cells of patients at advanced disease stages. This work provides, for the first time, evidence of immune activation in early stages of cutaneous melanoma, together with an increase of cells expressing CD158a in patients bearing the corresponding HLA-C ligand, which may be important to evaluate the disease progression and to use individualized immune therapeutic approaches.

Diagnostic Performance of Whole Body Dual Modality 18F-FDG PET/CT Imaging for N- and M-Staging of Malignant Melanoma: Experience With 250 Consecutive Patients

To assess the diagnostic performance of positron emission tomography/computed tomography (PET/CT) using (18)F-fluorodeoxyglucose (FDG) for N- and M-staging of cutaneous melanoma. This is a retrospective and blinded study of 250 consecutive patients (105 women, 145 men; age 58 +/- 16 years) who underwent FDG-PET/CT for staging of cutaneous melanoma at different time points in the course of disease. Whole-body FDG-PET/CT was performed 101 +/- 21 minutes postinjection of 371 +/- 41 MBq FDG. Diagnostic accuracy for N- and M-staging was determined for CT alone, PET alone, and PET/CT. PET/CT detected significantly more visceral and nonvisceral metastases than PET alone and CT alone (98.7%, 88.8%, and 69.7%, respectively). PET/CT imaging thus provided significantly more accurate interpretations regarding overall N- and M-staging than PET alone and CT alone. Overall N- and M-stage was correctly determined by PET/CT in 243 of 250 patients (97.2%; 95% CI, 95.2% to 99.4%) compared with 232 patients (92.8%; 95% CI, 89.6% to 96.0%) by PET, and 197 patients (78.8%; 95% CI, 73.7% to 83.9%) by CT. All differences were significant. Accuracy of PET/CT was significantly higher than that of PET and CT for M-staging (0.98 v 0.93 and 0.84) and significantly higher than that of CT for N-Staging (0.98 v 0.86). Change of treatment according to PET/CT findings occurred in 121 patients (48.4%). The diagnostic performance of FDG-PET/CT for N- and M-staging of melanoma patients suggests its use for whole-body tumor staging, especially for detection or exclusion of distant metastases.

The Utility of Magnetic Resonance Imaging in the Detection of Brain Metastases in the Staging of Cutaneous Melanoma

Aims To retrospectively evaluate the use of brain magnetic resonance imaging (MRI) in the initial staging of patients with cutaneous melanoma in our melanoma unit. Materials and methods The radiology request forms for brain MRI for melanoma staging for 193 consecutive patients were reviewed. Patient hospital records were also retrospectively reviewed. Patients with no histological confirmation of a cutaneous primary or patients whose scan was to primarily investigate their neurological symptoms were excluded. Records were also searched for incidental symptoms that may have been associated with brain metastases. Results One hundred patients were eligible. No patients were upstaged by MRI. Of a total of 33 patients already graded as stage IV by prior staging, 11 (33%) were found to have brain metastases. No patients graded less than stage IV were found to have brain metastases on MRI. Six out of 12 patients with incidental symptoms had metastases. Five patients graded as stage IV had asymptomatic brain metastases. Conclusion We recommend brain MRI only for patients with stage IV disease and for other patients with melanoma contemplating further adjuvant therapy where brain metastases would change management.

Melanoma of the head and neck

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.

Is completion lymphadenectomy after a positive sentinel lymph node biopsy for cutaneous melanoma always necessary?

Completion lymph node dissection (CLND) has usually been recommended after metastatic disease is identified in the sentinel lymph node (SLN) biopsy to eradicate further metastases in nonsentinel nodes. We hypothesized that patients with negative lymph nodes included in the initial SLN specimen have low risk of metastases in the residual draining basin and may not require CLND. Chart review. University-affiliated tertiary care referral center. Between January 1, 1997, and May 31, 2003, 506 consecutive patients underwent SLN biopsy for staging of primary cutaneous melanoma. The SLN biopsy identified 87 patients (17.2%) with metastatic melanoma, of whom 80 underwent CLND. In 28 patients, all SLNs were found to contain metastatic melanoma. Seven (25%) of these patients had additional metastases identified in the CLND specimen. In 52 patients, 1 or more SLNs did not contain metastatic melanoma. Five (10%) of these patients had additional metastases in the CLND specimen (P =.02). Although no evidence of metastatic melanoma was found on CLND in most patients in whom negative nodes had been removed with positive SLNs at the initial biopsy, 10% of these patients did have further metastases. This subgroup of patients (positive SLNs and negative nodes in the SLN biopsy specimen) is at significantly lower risk for further metastasis, but CLND cannot be safely omitted even for these patients.

Positron emission tomography is not useful in detecting metastasis in the sentinel lymph node in patients with primary malignant melanoma stage I and II.

The most powerful predictor for recurrence and survival in patients with primary malignant melanoma is the presence or absence of lymph node metastases. In the present study, 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) findings were compared with histopathological results of sentinel lymph node biopsy (SNB). The purpose was to determine the value of FDG-PET in predicting regional lymph node involvement in patients with primary malignant melanoma stage I and II. Forty-eight consecutive patients with primary cutaneous melanoma stage I (Breslow thickness > 1 mm) and II underwent FDG-PET scans, preoperative lymphoscintigraphy, and SNB. The FDG-PET and SNB results were interpreted independently of each other and then compared. Of the 48 patients included in the study, eight (16.7%) had a positive SNB. PET was positive in only one patient with a positive SNB, yielding a sensitivity of 13%. All other positive sentinel nodes could not be detected by metabolic FDG-PET imaging. Our study revealed that FDG-PET is obviously not an adequate screening test for subclinical and sonographically inconspicuous lymph node metastases in patients with malignant melanoma stage I and II. The low sensitivity is probably due to the small size of metastatic deposits in sentinel nodes. Therefore, SNB remains the technique of choice for evaluating the histological status of lymph node basins in patients with early-stage cutaneous melanoma.

Sentinel lymph node dissection and lymphatic mapping for local subcutaneous recurrence in melanoma treatment: longer-term follow-up results.

Lymphatic mapping and sentinel lymph node dissection (LM/SLND) for surgical staging of cutaneous primary melanoma is currently being evaluated, but the role of these techniques in recurrent (secondary) melanoma is largely unexplored. Our experience with 12 patients indicates the potential usefulness of LM/SLND in the management of locally recurrent melanoma at subcutaneous sites. We have even used mapping to localize the sentinel node draining a subcutaneous local recurrence after previous LM/SLND for primary melanoma. The application of LM/SLND may therefore be extended beyond primary melanoma management as we understand more about the technical issues and appropriate selection of patients.

Histopathological patterns of melanoma metastases in sentinel lymph nodes

Aims: Sentinel lymph node biopsy (SLNB) is an important component in the staging and treatment of cutaneous melanoma (CM). The medical literature provides only limited information regarding melanoma sentinel lymph...

The new TNM classification of malignant melanoma

The identification of increasingly powerful prognostic factors has led to sequential modifications of the cutaneous melanoma staging system. The American Joint Committee on Cancer (AJCC) recently proposed major revision of tumor node metastasis (TNM) categories and stage groupings for melanoma. The authors summarize the main characteristics of this new TNM classification of malignant melanoma. The importance of the novel technique - sentinel node biopsy - in the management of malignant melanoma is discussed.

A new animal model for the imaging of melanoma: correlation of FDG PET with clinical outcome, macroscopic aspect and histological classification in Melanoblastoma-bearing Libechov Minipigs.

The aim of this study was to evaluate the Melanoblastoma-bearing Libechov Minipigs (MeLiM) as an animal model of melanoma for in vivo imaging. Serial whole-body 2-deoxy-2-[(18)F]fluoro- d-glucose positron emission tomography (FDG PET) scans were conducted on five MeLiM. In order to explore different clinical stages of the tumoural lesions, each animal was scanned two to four times, at intervals of 30-155 days. PET images were analysed by a semiquantitative method based on the tumour to muscle metabolic ratio. Histology was performed on biopsies taken between or after the scans and the histological grading of the tumours was compared with the FDG uptake. The overall sensitivity of FDG PET for the detection of cutaneous melanoma was 75%; 62.5% of involved lymph nodes were positive. Sensitivity was better for tumours with vertical growth than for flat lesions. FDG PET did not detect tumours with epidermal involvement only, nor did it detect small metastatic foci. The metabolic ratio was correlated with the evolution of the melanoma. FDG PET is effective in the staging of cutaneous melanoma and the follow-up of tumoural extension and regression in Melanoblastoma-bearing Libechov Minipigs. The results obtained in this animal model correlate well with those described in human melanoma. Accordingly, this model may be useful in testing new tracers specific for melanoma and in helping to detect molecules expressed early during tumoural regression.

Reliability and accuracy of sentinel node biopsy in cutaneous malignant melanoma.

The aims of this study were 1) to investigate whether sentinel lymph node (SLN) biopsy could become the method of choice for the early detection of metastatic disease in patients with malignant melanoma and 2) to identify those patients with lymph node metastases who could benefit from regional lymphadenectomy. Our study started in March 1998 and involved 110 patients with primary cutaneous malignant melanoma stage I or II (AJCC) in whom the primary lesion had been surgically removed no more than 90 days previously. On the day of lymph node dissection patients were given an intradermal injection of colloid particles of human serum albumin labeled with technetium-99m and an injection of isosulfan blue. The surgical procedure was usually performed with local anesthesia but in some cases locoregional or general anesthesia was preferred. Contralateral and ipsilateral lymphatic areas were scanned with a hand-held gamma camera (Scintiprobe MR 100) to measure the background and identify the hot point indicating the location of the sentinel node to direct the incision. The combined use of lymphoscintigraphy, isosulfan blue and gamma probe allowed us to identify sentinel nodes in 108 of 110 patients (98.18%) while the SLN was blue in only 90 cases (81.81%). The SLN was positive for metastases in 13 of the 108 patients (12.03%) and regional and distal lymphadenectomy was performed in all of them. The distribution of positive SLNs by primary lesion thickness was as follows: 0.76-1.5 mm: one positive SLN/44 patients (2.27%); 1.51-4 mm: six positive SLNs/51 patients (11.7%); > 4 mm: six positive SLNs/15 patients (40%). Only four of 12 patients with ulcerated cutaneous melanoma had positive SLNs. The patients in our study underwent follow-up visits every four months. The median follow-up was 481 days (range, 97-1271 days). In patients with primary cutaneous melanoma the histological status of the SLN accurately reflects the presence or absence of metastatic disease in the relevant regional lymph node basin. Complete lymph node dissection should only be performed in patients with positive SLNs. Patients with lesions > 4 mm are likely to develop recurrences and to die of systemic disease, so in these patients the usefulness of SLN biopsy is questionable. In conclusion, sentinel node mapping is a rational approach for the selection of patients who might benefit from early lymph node dissection of the affected basin.

SPECT demonstrating lymphatic drainage from truncal melanoma to para-aortic lymph nodes.

Lymphoscintigraphy to identify the sentinel lymph node is a valuable adjunct for staging cutaneous melanoma. This technique may be particularly useful for truncal melanoma, because marked variability in drainage patterns has been reported. The authors report a case of melanoma of the back draining to three different nodal basins, including what were most likely para-aortic lymph nodes based on SPECT imaging.

Earlier diagnosis of second primary melanoma confirms the benefits of patient education and routine postoperative follow-up.

Rising health care costs have caused providers to question the benefit of regular follow-up after treatment for patients with early stage cutaneous melanoma. The authors hypothesized that routine reassessment and careful education of these patients would facilitate earlier diagnosis of a subsequent second primary melanoma, as reflected by reduced thickness of that lesion. A prospective melanoma data base was used to identify patients who developed a second primary melanoma after treatment for American Joint Committee on Cancer (AJCC) Stage I or II cutaneous melanoma. After excision of the initial primary melanoma, all patients underwent routine biannual follow-up for new primary lesions. Follow-up consisted of a questionnaire and a complete skin examination by a physician. In addition, patients were regularly educated regarding the increased risk of developing a second melanoma. A paired t test was used to examine AJCC stage, thickness, and level of invasion of the initial melanoma compared with the second primary melanoma. Of 3310 patients with AJCC Stage I or II melanoma, 114 patients (3.4%) developed a second primary melanoma. AJCC staging of both first and second melanomas was available in 82 patients (72%). When the AJCC stages of first and second melanomas were compared, 39 of 82 patients (48%) had lower stage second primary lesions, and 41 (50%) had same-stage second primary lesions. The mean tumor thickness was 1.32 +/- 1.02 mm for the initial melanoma, decreasing to 0.63 +/- 0.52 mm for the second melanoma; in fact, tumor thickness increased in only 4 of 51 patients (8%) whose records contained data for both first and second melanomas. Similarly, the level of invasion decreased in 60% of patients, remained the same in 27% of patients, and increased in only 13% of patients. By paired t test, the differences in AJCC stage, tumor thickness, and level of invasion between first and second melanomas were each highly significant (P = 0.0001). In this study, the second primary melanoma in patients with a prior cutaneous melanoma was significantly thinner than the initial primary lesion. This is evidence that careful follow-up and patient education allow earlier diagnosis. All patients diagnosed with cutaneous melanoma should be counseled regarding the risks of second melanoma and should undergo lifelong follow-up at biannual intervals.

Clinical Classification And Staging

The identification of increasingly powerful prognostic factors has led to sequential modifications of the cutaneous melanoma staging system. Changes in the staging system are anticipated as more refined prognostic factors are identified. This article provides an overview of the system, including a brief history and an introduction to recent advances in staging of patients with primary melanoma (i.e., sentinel lymphadenectomy). Practical recommendations for a stage-specific workup for the patient, which are especially important given the need for quality care in an increasingly cost-conscious environment, are provided.

CLASSIFICATION AND STAGING OF MELANOMA

Although a standardized and uniformly accepted cancer staging system is an essential and fundamental requirement to enable meaningful comparisons across patient populations, the sometimes capricious biologic behavior of melanoma makes developing such a staging system particularly difficult. Since the earliest well-documented attempts at classifying patients with cutaneous melanoma were described more than 50 years ago, the identification of increasingly powerful prognostic factors has led to sequential modifications of the cutaneous melanoma staging system. The current AJCC staging system is based on relatively well-established prognostic factors; however, several recent reports have identified additional prognostic factors not included in the current system, and other studies support the re-evaluation of some of the currently employed staging criteria. Some of the more controversial areas include the relevance of level of invasion versus tumor thickness, optimal cutoffs for tumor thickness, importance of ulceration, the grouping of satellites with in-transit metastases, the inclusion of microsatellites and local recurrences as a separate staging criterion, the replacement of size of nodal mass with number of positive nodes, the importance of nodal metastases in more than one nodal basin, and the prognostic significance of distant metastases. Therefore, future modifications of the staging system are anticipated to better incorporate these observations. Stage-specific staging recommendations for the patient with melanoma provide the clinician with a framework to most efficiently assess extent of disease in an era of cost-conscious clinical practice. In the asymptomatic patient with primary melanoma (stage I or II), we recommend a chest roentgenogram and evaluation of alkaline phosphatase and LDH levels; extensive radiologic evaluations are not indicated, because the rate of detection in this population is extremely low. Additional staging information should also be obtained by the technique of lymphatic mapping and sentinel lymphadenectomy. For patients with local-regional disease (stage III, satellites, and local recurrence), a selective approach to imaging studies is warranted. For this patient population, we recommend complete blood count, liver function tests including alkaline phosphatase and LDH, a chest roentgenogram, and a CT scan of the abdomen. Although the yield of these tests, particularly CT of the abdomen, in detecting distant metastases in asymptomatic patients is low, they may identify false-positive abnormalities and provide an important baseline for future studies in this high-risk population. For patients with disease below the waist or in the head and neck region, we recommend CT of the pelvis and CT of the neck, respectively. Additional studies should be done only if clinically indicated. Finally, patients with known systemic disease (stage IV) should be more comprehensively evaluated, because the likelihood of detecting asymptomatic metastases is higher. Accordingly, in addition to the work-up outlined previously for stage III patients, we also perform a CT scan of the chest and MR imaging of the brain; other studies (e.g., bone scan, gastrointestinal series) are performed on the basis of symptoms.