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The staging of melanoma has undergone tremendous revision and change since the initial pathologic descriptions of the disease. Here, the recent AJCC revisions are included. In addition, there is an ever burgeoning collection of prognostic factors that may lead to improved surveillance and treatment for this deadly disease.



Activated Serine-Threonine Protein Kinas B (p-Akt)
Adhesion molecules
AgNOR Counts
Childhood melanomas
Fatty Acid Synthase Expression
Growth rate
Incisional biopsykit
Ki-67 (MIB-1)
Lymphovascular Invasion
Mast cells
Melastatin mRNA
Mitotic Rate
Poly Polymerase 1
Solitary melanoma confined to dermis or subcutaneous fat
Thick melanomas
Thin melanomas
TrkA Protein
Tumor infiltrating lymphocytes
Vascular involvement
Vasculogenic mimicry

Commonly Used Terms  
Internet Links  


(2002 American Joint Committee on Cancer Staging System)

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

Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF.

Johns Hopkins Medical Institutions, Baltimore, MD, USA.

J Clin Oncol 2001 Aug 15;19(16):3635-48 Abstract quote

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.

Evaluation of staging chest radiographs and serum lactate dehydrogenase for localized melanoma.

Wang TS, Johnson TM, Cascade PN, Redman BG, Sondak VK, Schwartz JL.

Department of Dermatology, University of Michigan Health System, University of Michigan Comprehensive Cancer Center, USA.
J Am Acad Dermatol. 2004 Sep;51(3):399-405. Abstract quote  

BACKGROUND: Radiographic and laboratory evaluations are often routinely used in the initial work-up for melanoma.

PURPOSE: To examine the yield of a chest radiograph and serum lactate dehydrogenase (LDH), in the work-up for newly diagnosed localized melanoma.

METHODS: Patients with a new diagnosis of localized invasive melanoma were entered into a prospective database. The status of the chest radiograph, LDH, and sentinel lymph node (SLN) was assessed.

RESULTS: Two-hundred-twenty-four patients were entered into the study and 210 had chest radiograph data for analysis. The true positive chest radiograph rate, defined as the percent of chest radiographs interpreted as "positive or equivocal possibly melanoma related" with subsequent confirmed melanoma metastases, was 0%. The false positive chest radiograph rate, defined as the percent of chest radiographs interpreted as "positive or equivocal possibly melanoma related" with melanoma metastases excluded based on previous or subsequent studies or other known medical conditions, was 7%. Ninety-six patients (melanoma> or =1 mm) had LDH results for analysis. Elevations in LDH were found in 15% and did not lead to detection of occult disease in any patients. Seventy-seven patients underwent SLN biopsy. A positive SLN did not correlate with abnormal chest radiograph or LDH.

CONCLUSION: Low yield, high rate of false-positive tests and lack of significant impact of early detection of metastases on survival argue that chest radiographs and serum lactate dehydrogenase should probably not be accepted into routine clinical practice in patients with clinically localized melanoma in the absence of data supporting their use.


COMPARISON OF THE 1997 AND 2002 STAGING SYSTEMS (Adapted from Skin and Aging 2002:39.)
Thickness Secondary prognostic factor; thresholds of 0.75, 1.50, and 4.0 mm Primary determinant of T staging; thresholds of 1.0, 2.0, 4.0 mm Correlation of metastatic risk is a continuous variable
Level of invasion Primary determinant of T staging Used only for defining T1 melanomas Correlation only significant for thin lesions; variability in interpretation
Ulceration Not included Included as second determinant of T and N staging Signifies a locally advanced lesion; dominant prognostic factor for grouping Stages I, II, III
Satellite metastases In T category In N category Merged with in-transit lesions
Thick melanomas (>4mm) Stage III Stage IIC Stage II defined as regional metastases
Dimensions of nodal metastases Dominant determinant of N staging Not used No evidence of significant prognostic correlation
Number of nodal metastases Not included Primary determinant of N staging Thresholds of 1 vs. 2-3 vs. greater than or equal to 4 nodes
Metastatic tumor burden Not included Included as a second determinant of N staging Clinically occult (microscopic) vs. clinically apparent (macroscopic) nodal volume
Lung metastases Merged with all other visceral metastases Separate category as M1b Has a somewhat better prognosis than other visceral metastases
Elevated serum LDH Not included Included as a second determinant of M staging  
Clincal vs. pathologic staging Did not account for sentinel node technology Sentinel node results incorporated into definition of pathologic staging Large variability in outcome between clinical and pathologic staging; pathologic staging encouraged prior to entry into clinical trials


0 Intraepithelial/in situ melanoma (TisN0M0)   100% 100%
IA </= 1 mm without ulceration and Clark level II/III (T1aN0M0)   95% 88%
IB </= 1 mm with ulceration or level IV/V (T1bN0M0)   91% 83%
1.01-2 mm without ulceration (T2aN0M0)   89% 79%
IIA 1.01-2 mm with ulceration (T2bN0M0)   77% 64%
2.01-4 mm without ulceration (T3aN0M0)   79% 64%
IIB 2.01-4 mm with ulceration (T3bN0M0)   63% 51%
>4 mm without ulceration (T4aN0M0)   67% 54%
IIC >4 mm with ulceration (T4bN0M0)   45% 32%
IIIA Single regional nodal micrometastasis, nonulcerated primary
  69% 63%
2-3 microscopic regional nodes, nonulcerated primary (T1-4aN2aM0)   63% 57%
IIIB Single regional nodal micrometastasis, ulcerated primary (T1-4bN1aM0)   53% 38%
2-3 microscopic regional nodes, ulcerated primary (T1-4bN2aM0)   50% 36%
Single regional nodal macrometastasis, nonulcerated primary (T1-4aN1bM0)   59% 48%
2-3 macroscopic regional nodes, nonulcerated primary (T1-4aN2bM0)   46% 39%
In-transit met(s)/satellite lesion(s) without metastatic lymph nodes (T1-4a/bN2cM0)   30-50%  
IIIC Single macroscopic regional node, ulcerated primary (T1-4bN1bM0)   29% 24%
  2-3 macroscopic regional nodes, ulcerated primary (T1-4bN2bM0)   24% 15%
  4 or more metastatic nodes, matted nodes/gross extracapsular extension, or in-transit met(s)/satellite(s) and metastatic ndoes (any T N3M0)   27% 18%
IV Distant skin, subcutaneous, or nodal mets with normal LDH
(any T any N M1a)
59% 19% 16%
  Lung mets with normal LDH (any T any N M1b) 57% 7% 3%
  All other visceral mets with normal LDH or any distant mets with increased LDH (any T any N M1c) 41% 9% 6%


Stage Characterization
pTX Primary tumor cannot be assessed (shave biopsy, regressed melanoma)
pT0 No evidence of primary tumor
pTis Melanoma in situ, not an invasive lesion
pT1 Tumor </= 1.0 mm or less in thickness with or without ulceration
pT1a Tumor </= 1.0 mm or less in thickness and level II or III, without ulceration
pT1b Tumor </= 1.0 mm or less in thickness and level IV or V, or with ulceration
pT2 Tumor 1.01-2.0 mm in thickness with or without ulceration
pT2a Tumor 1.01-2.0 mm in thickness without ulceration
pT2b Tumor 1.01-2.0 mm in thickness with ulceration
pT3 Tumor 2.01-4.0 mm in thickness with or without ulceration
Tumor 2.01-4.0 mm in thickness with or without ulceration
Tumor 2.01-4.0 mm in thickness with ulceration
pT4 Tumor more than 4 mm in thickness with or without ulceration
Tumor more than 4 mm in thickness without ulceration
Tumor more than 4 mm in thickness with ulceration


Stage Characterization
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastases in one lymph node
Clinically occult (microscopic) metastasis
N2 Metastases in two to three regional nodes or intralymphatic regional metastasis without nodal metastasis
Clinically occult (microscopic) metastasis
Clinically apparent (macroscopic) metastasis
Satellite or in-transit metastases without nodal metastasis
N3 Metastasis in four or more regional nodes, or matted metastatic nodes, or in-transit metastasis or satellite(s) with metastasis in regional node(s)


Stage Characterization
MX Presence of distant metastases cannot be assessed
M0 No distant metastases
M1 Distant Metastases
Distant metastases in skin or subcutaneous tissue or distant lymph node(s)
Metastasis to lung
Metastasis to all other visceral sites or distant metastasis at any site associated with an elevated serum lactic dehydrogenase (LDH)


Stage Characterization
0 Tis, N0, M0
IA T1a, N0, M0
IB T1b, N0, M0
T2a, N0, M0
IIA T2b, N0, M0
T3a, N0, M0
IIB T3b, N0, M0
T4a, N0, M0
IIC T4b, N0, M0
IIIA T1-4a, N1a, M0
T1-4a, N2a, M0
IIIB T1-4b, N1a, M0
T1-4b, N2a, M0
T1-4a, N1b, M0
T1-4a, N2b, M0
T1-4a/b, N2c, M0
IIIC T1-4b, N1b, M0
T1-4b, N2b, M0
Any T, N3, M0
IV Any T, Any N, M1



These parameters have been cited as having prognostic significance:

Vertical growth phase
Depth of invasion
Angiolymphatic invasion
Mitotic activity
Host response

Downregulation of cell cycle modulators p21, p27, p53, Rb and proapoptotic Bcl-2-related proteins Bax and Bak in cutaneous melanoma is associated with worse patient prognosis: preliminary findings.

Department of Dermatology and Allergy, Medical University Charite-Berlin, Skin Cancer Center, Campus Benjamin Franklin, Berlin D-14195, Germany.


J Cutan Pathol. 2007 Mar;34(3):247-56. Abstract quote

Background: Cutaneous melanoma is a tumor with high metastatic potential, but the mechanisms leading to progression are still not fully understood. To provide further molecular basis for understanding the progression of melanoma, the aim of this study was to examine the expression pattern of cell cycle modulators (p21, p27, p53 and Rb) and proapoptotic multidomain Bcl-2 related proteins (Bax and Bak) and to analyze its differences in patients with and without progression stages.

Methods: We have studied 31 patients with cutaneous melanoma at stage IIa (Breslow thickness 1.5-4.0 mm), and follow them for 10-year period. Eighteen of these patients developed metastasis. The determination of selected molecular markers participating in cell cycle regulation and apoptosis was performed by immunohistochemistry.

Results: We have observed a significant increase in the loss of expression of the Bax, Bak, p21, p27, p53 and Rb. The analysis of the relationship between these downregulated markers and Breslow thickness showed significant positive correlation (r = 0.556, p = 0.029) and predictive value if thickness below 2.3 mm (OR = 3.0, 95% CI = 0.312-28.84).

Conclusions: Our study showed that the downregulation of the markers associated with cell cycle control and apoptosis is of great value in predicting malignant transformation and in assessing the risk of metastases development for 10-year follow-up period.
Breslow depth of cutaneous melanoma: impact of factors related to surveillance of the skin, including prior skin biopsies and family history of melanoma.

Fisher NM, Schaffer JV, Berwick M, Bolognia JL.

Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

J Am Acad Dermatol. 2005 Sep;53(3):393-406. Abstract quote  

BACKGROUND: Because the early detection of cutaneous melanoma can dramatically improve survival, identification and surveillance of persons at risk have received much attention.

OBJECTIVE: Our purpose was to examine the influences of personal or family history, patterns of detection, and prior skin biopsies (considered to be a measurement of surveillance by medical personnel) on the Breslow depth of cutaneous melanomas.

METHODS: A retrospective cohort analysis of 218 patients with a history of at least one invasive cutaneous melanoma who visited the Yale Pigmented Lesion Clinic between January 1995 and January 1996 was performed. Data on patterns of detection, melanocytic nevi, and skin biopsies before and after the initial diagnosis of melanoma were collected, and patients with a family history of melanoma were compared with sporadic patients.

RESULTS: Initial melanomas discovered by dermatologists were more likely to be 0.75 mm or less in depth than those found by other physicians (P = .03). Although patients detected 45% of the initial primary melanomas (98/218), dermatologists discovered 80% of the second primary tumors (33/41; P = .001). A personal history of melanoma was predictive of a thinner Breslow depth (P = .01), but a family history of melanoma was not. Having a biopsy of any type or combination of types of skin lesion(s) performed in the 5 years, 2 years, or 1 year before the first diagnosis of melanoma did not predict a melanoma of thinner Breslow depth among either familial or sporadic patients. The mean number of skin biopsies performed per patient was 8 times higher in the 5-year period after (5.6) versus the 5-year period before (0.7) the initial diagnosis of melanoma, with a peak in the first year after the diagnosis (2.3 vs 0.25 in the prior year). In 27 patients, one or more skin biopsies were performed in the year before the initial diagnosis of melanoma; 41% of these biopsies (23/56) were of lesions in normally exposed sites (eg, the face, neck, and forearms) compared with 22% of the melanomas (6/27).

LIMITATIONS: Since an invasive melanoma (with the possible exception of a nodular melanoma) would likely have been present for at least a year, plausible explanations for why evidence of previous dermatologic care did not appear to result in earlier detection include performance of a limited rather than a total body skin examination as well as subtle clinical features of early melanomas. However, this study cannot give weight to these explanations because at the time new Pigmented Lesion Clinic patients were not routinely asked about previous total body skin examinations.

CONCLUSIONS: The disappointing trends seen in this study, with neither the well-established risk factor of a family history of melanoma nor previously having a skin biopsy predicting thinner melanomas, highlight the need to establish criteria defining the subset of patients for whom appropriate management requires periodic total body skin examination.
Molecular diagnostics in melanoma.

Carlson JA, Ross JS, Slominski A, Linette G, Mysliborski J, Hill J, Mihm M Jr.

Division of Dermatopathology, Albany Medical College, Albany, New York 12208, USA.
J Am Acad Dermatol. 2005 May;52(5):743-75; quiz 775-8. Abstract quote  

Molecular pathology is rapidly evolving, featuring continuous technologic improvements that offer novel clinical opportunities for the recognition of disease predisposition, for identifying sub-clinical disease, for more accurate diagnosis, for selecting efficacious and non-toxic therapy, and for monitoring of disease outcome.

Currently, the identification and prognosis of primary cutaneous melanoma is based on histologic factors (tumor depth and ulceration) and clinical factors (number of lymph node and/or distant metastases). However, metastasis can occur in patients with thin melanomas, and sentinel lymph node biopsy does not identify all patients at risk for distant metastasis.

New markers exist that correlate with melanoma progression, which may aid in melanoma identification, prognostication, and detection of minimal residual disease/early recurrence. Moreover, not many therapeutic options exist for melanoma as no regimen prolongs survival. Emerging data with investigational therapies suggest that certain markers might play a crucial role in identifying patients who will respond to therapy or show utility in the monitoring the response to therapy.

Herein, molecular diagnostics that can potentially benefit the individual melanoma patient will be discussed.

Lack of Relevant Information for Tumor Staging in Pathology Reports of Primary Cutaneous Melanoma

Klaus J. Busam

Am J Clin Pathol 2001;115:743-746 Abstract quote

For the T classification of primary cutaneous melanoma, the current American Joint Committee on Cancer staging (AJCC) system relies on tumor thickness and level of invasion. A new T classification has been proposed based on thickness and ulceration. The slides and reports of 135 departmental pathology consultations of patients referred to a major cancer center with a diagnosis of primary cutaneous invasive malignant melanoma were examined. Whether the outside pathology reports contained information on tumor thickness, level of invasion, and ulceration was recorded. Dermatopathologists had issued 76.3% of the reports and general surgical pathologists, 24.3%. Information provided was as follows: tumor thickness, 97.8%; Clark level, 71.9%; and presence or absence of ulceration, 28.1%. Of the 97 melanomas with no comment on ulceration, 17 were indeed ulcerated. Thus, the lack of a comment on ulceration cannot be equated with the absence of ulceration.

The present study documents that many pathology reports on melanomas lack sufficient information for AJCC staging. Therefore, review of outside pathology material is necessary not only to confirm or revise the tumor diagnosis but also to provide clinicians with histologic parameters required for AJCC staging.

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.

Tuthill RJ, Unger JM, Liu PY, Flaherty LE, Sondak VK; Southwest Oncology Group.

Department of Anatomic Pathology, Cleveland Clinic Foundation, OH 44195, USA.

Am J Clin Pathol 2002 Oct;118(4):504-11 Abstract quote

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%.

Expression of Activated Akt and PTEN in Malignant Melanomas : Relationship With Clinical Outcome.

Slipicevic A, Holm R, Nguyen MT, Bohler PJ, Davidson B, Florenes VA.

Department of Pathology, the Norwegian Radium Hospital, University of Oslo, Oslo, Norway.

Am J Clin Pathol. 2005 Oct;124(4):1-9. Abstract quote  

Our purpose was to analyze, by immunohisto-chemistry, the expression of activated serine-threonine protein kinase B (p-Akt) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in benign nevi and primary and metastatic melanomas and to correlate the expression level with clinical variables.

We observed cytoplasmic and/or nuclear expression of p-Akt in 22 (54%) of 41 benign nevi, 112 (71.3%) of 157 primary tumors, and 50 (71%) of 70 metastases. Cytoplasmic PTEN staining was observed in 0 (0%), 152 (87.7%), and 64 (90%) of 41 nevi, 162 primary tumors, and 71 metastases, respectively. A significant positive correlation was seen between PTEN and p-Akt cytoplasmic expression (P < .001) in primary melanomas. Cytoplasmic p-Akt expression showed a positive association with cyclin A in superficial spreading (P = .038) but not in nodular (P = .22) melanomas.

Cytoplasmic p-Akt and PTEN expression did not have an impact on disease-free and overall survival, but complete lack of nuclear p-Akt expression was a predictor of shorter disease-free survival (P = .025) for patients with superficial spreading melanoma.

J Natl Cancer Inst 1995;87:366-371

Increasing tumor thickness associated with expression of very late activation (VLA-4) in tumor cells increased with a concomitant decrease in VLA-6 expression

VLA-4 correlates significantly with metastases

Intratumoral vessels staining positive for ELAM-1 (E-selectin) and CD62 (P-selectin) and melanoma cells positive for VLA-4 correlated with decreased disease free survival and overall survival time


Argyrophilic staining of nucleolar organizer region count and morphometry in benign and malignant melanocytic lesions.

Li LX, Crotty KA, Palmer AA, Kril JJ, Scolyer RA, Thompson JF, McCarthy SW.


Am J Dermatopathol. 2003 Jun;25(3):190-7. Abstract quote

Differentiation between malignant melanomas (MMs) and benign nevi based on histologic features can sometimes be difficult.

This study evaluated the diagnostic effectiveness of argyrophilic staining of nucleolar organizer regions (AgNORs) in separating benign nevi from MMs by assessing 27 compound nevi (CN), 20 dysplastic nevi (DN), 10 Spitz nevi (SN), and 24 MMs. Both AgNOR count and morphology variables were measured from the superficial, middle, and deep zones of the lesions using video image analysis. Malignant melanomas had a significantly greater AgNOR number per nucleus, mean AgNOR area per nucleus, and variation in AgNOR area per nucleus compared with all types of benign nevi (p < 0.05). In multivariate discriminant analysis using a combination of four AgNOR counts and morphometric parameters, all CN and DN, 8 of 10 SN, and 23 of 24 MMs could be correctly classified as benign or malignant.

The results suggest that both AgNOR count and morphology help to separate benign and malignant melanocytic lesions and that the combination of both sets of parameters improves their discriminating ability.

CD10 protein expression in tumor and stromal cells of malignant melanoma is associated with tumor progression.

Bilalovic N, Sandstad B, Golouh R, Nesland JM, Selak I, Torlakovic EE.

1Department of Pathology, University Hospital Sarajevo, Bosnia and Herzegovina.

Mod Pathol. 2004 Oct;17(10):1251-8. Abstract quote  

CD10 antigen is a 100-kDa-cell surface zinc metalloendopeptidase expressed in a variety of normal and neoplastic lymphoid and nonlymphoid tissues including melanomas. It was recently shown that metastatic melanomas express more CD10 than primary tumors.

We evaluated CD10 expression in tumor and stromal cells in 70 biopsies with primary and 28 with metastatic malignant melanomas. Ki-67, Bcl-2, and Bax were also examined to investigate whether CD10 expression is associated with tumor proliferation index or factors of apoptosis. Formalin-fixed/paraffin-embedded tissues were studied by immunohistochemistry. More advanced primary tumors had higher CD10 expression in the tumor cells (r=0.27, P=0.03 for Clark levels and r=0.29, P=0.02 for Breslow) and higher Ki-67 proliferation fraction (r=0.32, P=0.007 for Clark levels and r=0.32, P=0.001 for Breslow). Similarly, CD10 expression in the intratumoral stromal cells was also higher in primary tumors with higher Clark level (P=0.04, linear-by-linear association) and tumor thickness according to Breslow (r=0.33, P=0.01).

The presence of CD10+ peritumoral stromal cell cuffs was also positively associated with tumor thickness according to Breslow (r=0.27, P=0.05). Also, expression of CD10 and Ki-67 were significantly higher in metastatic than in primary tumors (P=0.01 and 0.02 respectively), but Bcl-2 expression was higher in primary melanomas (P=0.02). We conclude that CD10 expression in malignant melanoma is associated with tumor progression.

Eur J Cancer 1997;33:926

Tumors with high levesl had significantly reduced 5 YRS compared to those with low levels


Melanomas in prepubescent children: review comprehensively, critique historically, criteria diagnostically, and course biologically.

Mones JM, Ackerman AB.


Am J Dermatopathol. 2003 Jun;25(3):223-38. Abstract quote

Our series was comprised of 11 children age 10 years or younger (6 were younger than age 5) with primary cutaneous melanoma. All of the melanomas occurred de novo and all metastasized; one child died. In no instance was melanoma a clinical consideration, and in none did the histopathologist who first "signed out" the case make a diagnosis of melanoma.

Despite the inability of clinicians and pathologists to diagnose correctly, with repeatability, melanomas that develop in children yet to be pubescent, those neoplasms, nonetheless, are melanomas and, therefore, criteria employed currently for diagnosis of melanoma, especially clinically, must be refined in order that they be applicable equally to melanomas in pre- and postpubescents.

The vaunted ABCDs (Asymmetry, Border irregular, Color variability, Diameter >6.0mm) surely do not work for melanomas that appear in children who are prepubescent. Additionally, melanomas that occur in these children have distinctly different architectural and cytopathological features from those that arise in postpubescents, often being confused as they are by conventional microscopy with a Spitz's nevus.

As a rule, melanomas in prepubescent children grow much more rapidly then those in adults but, like them, have the capability to disseminate widely and cause death.

Congenital and infantile melanoma: review of the literature and report of an uncommon variant, pigment-synthesizing melanoma.

Richardson SK, Tannous ZS, Mihm MC Jr.

Dermatopathology Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114-2696, USA

J Am Acad Dermatol 2002 Jul;47(1):77-90 Abstract quote

Congenital and infantile types of melanoma are uncommon conditions for which there are limited epidemiologic data. The number of reported cases is small with several ascribed etiologies.

We review the literature and report the first documented case, to our knowledge, of pigment-synthesizing melanoma in an infant. Reported cases of congenital and infantile melanoma were identified and categorized on the basis of disease origin. Dermatopathologic specimens from an infant given a diagnosis of pigment-synthesizing melanoma are described. Disease arising from medium and large/giant congenital nevi was most common, whereas reports of de novo and transplacental disease were infrequent. Death of approximately 40% of patients was noted within 18 months of diagnosis. Male infants accounted for approximately 74% of cases. The most commonly affected anatomic sites were the head and neck.

The prognosis for congenital and infantile melanoma is poor. The high incidence of head-and-neck involvement and male predominance for disease suggest dispositions for both anatomic disease localization and sex.

Childhood melanoma survival.

Saenz NC, Saenz-Badillos J, Busam K, LaQuaglia MP, Corbally M, Brady MS.

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Cancer 1999 Feb 1;85(3):750-4 Abstract quote

BACKGROUND. Melanoma in childhood is uncommon. Some believe that melanoma among children is associated with a better prognosis than among adults.

METHODS. The authors reviewed their institutional experience with melanoma in 40 patients younger than 18 years treated between 1950 and 1984. All slides were reviewed by a single dermatopathologist who was blinded to clinical outcomes. Long term follow-up was available for all but three patients.

RESULTS. There were 26 girls and 14 boys. The median age at diagnosis was 15 years (range, 3-17 years). Eleven patients (28%) were younger than 12 years. Fifteen patients (38%) had melanoma arise in a congenital nevus (2 had bathing trunk nevi. The most common site was the extremity (n = 23), followed by the trunk (n = 10) and the head and neck (n = 7). Seventeen patients (43%) initially were considered to have benign lesions, and 23 patients (57%) were diagnosed correctly with melanoma at initial presentation. Only 21 of 37 evaluable patients (57%) were alive at last follow-up with a median follow-up of 18 years (range, 2-48 years). Fifteen patients (41%) died of their disease, with a median survival of 12 months (range, 6-60 months). One patient died of breast carcinoma 14 years after treatment for melanoma. Disease free survival was 57% at 5 and 10 years. Of the 15 patients who died of disease, 12 were female (P = 0.09) and 10 had melanoma arising in a congenital nevus (P < 0.05). Five-year overall survival was 78% for patients who presented with localized disease (n = 23) and 30% for patients who presented with regional metastasis (n = 16, P < 0.001). There were no survivors among those who presented with systemic disease (n = 1).

CONCLUSIONS. Children with melanoma are at significant risk of dying of their disease. Survival is similar to that seen among adults and depends on stage at presentation. The survival advantage observed for adult females is not seen among children.

Prepubertal malignant melanoma: report of three cases.

Strojan P, Lamovec J.

Department of Radiotherapy, Institute of Oncology, Ljubljana, Slovenia.

Pediatr Hematol Oncol 2000 Mar;17(2):163-9 Abstract quote

Prepubertal malignant melanoma (MM) is an extremely rare tumor.

In Slovenia, 13 MM cases were registered between 1968 and 1996 by the Cancer Registry of Slovenia. The diagnosis of MM was confirmed by histology in 3 children. In 3 other children the lesions initially diagnosed as MM were reclassified as Spitz nevus. In the remaining cases, the slides were not accessible for histological review, and the clinical course of disease corroborated the diagnosis of a benign nevus.

In the present report, 3 of 13 cases with histologically confirmed prepubertal MM are described. The difficulties encountered in the diagnosis and management of this rare condition are discussed.

Reliability of the histopathologic diagnosis of malignant melanoma in childhood.

Wechsler J, Bastuji-Garin S, Spatz A, Bailly C, Cribier B, Andrac-Meyer L, Vergier B, Fraitag S, Verola O, Wolkenstein P.

Department of Dermatology, Henri-Mondor Hospital, F-94010 Creteil CEDEX, France.

Arch Dermatol 2002 May;138(5):625-8 Abstract quote

OBJECTIVE: To assess interrater reliability in the diagnosis of malignant melanoma in children.

DESIGN, SETTING, AND PARTICIPANTS: We collected 85 slides of melanomas diagnosed in patients younger than 17 years through a network of dermatopathologists and dermatologists. The slides were classified into 3 categories: (1) slides from children with metastatic melanoma; (2) slides from disease-free children with a follow-up of less than 5 years; (3) slides from disease-free children with a follow-up of 5 years or longer. Category 1 was considered the gold standard. Four pairs of expert dermatopathologists reviewed the slides and classified them into melanoma, nevus (including Spitz nevus), or ambiguous tumors.


MAIN OUTCOME MEASURE: Concordance between pairs of experts.

RESULTS: For category 1 slides (n = 20), the concordance was weak to moderate. For category 2 slides (n = 47), the concordance was weak. For category 3 slides (n = 18), the concordance was poor to moderate.

CONCLUSION: This study demonstrates that the reliability of diagnosis of melanoma in childhood is poor, even when submitted to experts.

Cutaneous melanoma in childhood and adolescence: An analysis of 36 patients.

Schmid-Wendtner MH, Berking C, Baumert J, Schmidt M, Sander CA, Plewig G, Volkenandt M.

Department of Dermatology and Allergology and Tumor Registry, Department of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich.

J Am Acad Dermatol 2002 Jun;46(6):874-9 Abstract quote

Analysis of data of 6931 patients with cutaneous melanoma seen at the Department of Dermatology and Allergology at the Ludwig-Maximilians-University of Munich between 1977 and 1998 identified 36 patients in whom cutaneous melanomas developed during childhood or adolescence (age <18 years).

Clinical courses of all patients and histopathologic characteristics of the lesions were reviewed. Seventeen patients were boys and 19 patients were girls. The median ages of the boys and girls were 15 and 16 years, respectively (range, 2-17 years). Thirty-one patients presented with nonmetastatic primary melanomas and 5 patients presented with metastatic melanoma. Forty-seven percent of the primary lesions were associated with a nevus (22% with congenital nevi and 25% with acquired nevi). Tumor thickness ranged from 0.24 to 7.0 mm, with a median of 1.29 mm (mean, 1.67 mm). All patients with primary melanomas received surgical therapy; patients with metastatic disease received chemotherapy, radiation therapy, or both. Relative 5-year survival was 87.5% for the group of patients younger than 18 years. Similar to experience in adult patients, survival strongly correlated with tumor thickness and clinical stage at the time of diagnosis.

The data emphasize that a high index of suspicion for cutaneous melanoma is needed by clinicians assessing melanocytic lesions in children and adolescents for early diagnosis. Reduction of the melanoma mortality rate in children and adolescents will be achieved through identification of patients at increased risk.

Cutaneous melanoma and atypical Spitz tumors in childhood.

Barnhill RL, Flotte TJ, Fleischli M, Perez-Atayde A.

Department of Pathology, Brigham and Women's Hospital, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Cancer 1995 Nov 15;76(10):1833-45 Abstract quote

BACKGROUND. Malignant melanoma in childhood is rare. As a result, the biology and natural history of melanoma in this age group is still poorly understood. Although the majority of Spitz nevi are benign regardless of atypical features, a particular problem is the continued confusion of Spitz nevi with atypical features with melanoma and the lack of specific criteria for their distinction. The latter discrimination is perhaps not so difficult when Spitz nevi are minimally atypical; however, the greater the atypia, the more challenging is this discrimination.

METHODS. All cases of malignant melanoma referred to Children's Hospital (Boston, MA) and to one of the authors were examined during the period of 1959-1995. Criteria for inclusion in the study included: (1) age up to 15 years; (2) availability of microscopic slides; and (3) availability of demographic data.

RESULTS. There were 11 males and 12 females, ranging in age from 2 to 15 years (mean age, 9.4 years). Histopathologically, the 23 tumors were categorized into four subgroups: (1) small cell melanoma (5); (2) adult-like melanoma (6); (3) Spitz-like melanoma (3), and (4) atypical Spitz tumors (9). The small cell melanomas were notable for localization to the scalp, significant thickness, and fatal outcome. The adult-like melanomas resembled typical tumors occurring in adults. The one fatal Spitz-like melanoma was located on the neck of a 14-year-old male. Two tumors in this group metastasized to regional lymph nodes, but were not associated with further aggressive disease on follow-up despite treatment with surgical excision only. The atypical Spitz tumors were characterized by significant thickness and abnormal features including prominent cellularity and mitotic activity.

CONCLUSIONS. Anatomic site and cell type may be important prognostic factors in addition to tumor thickness for childhood melanoma, but these tumors require further study. In addition, the biologic potential of atypical Spitz tumors has not been characterized sufficiently.


Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases.

Kraehn GM, Utikal J, Udart M, Greulich KM, Bezold G, Kaskel P, Leiter U, Peter RU.

Department of Dermatology, University of Ulm, Ulm, Germany.

Br J Cancer 2001 Jan 5;84(1):72-9 Abstract quote

Amplification and overexpression of the c-myc gene have been associated with neoplastic transformation in a plethora of malignant tumours.

We applied interphase fluorescence in situ hybridization (FISH) with a locus-specific probe for the c-myc gene (8q24) in combination with a corresponding chromosome 8 alpha-satellite probe to evaluate genetic alterations in 8 primary melanomas and 33 advanced melanomas and compared it to 12 melanocytic nevi, 7 safety margins and 2 cases of normal skin. Additionally, in metaphase spreads of 7 melanoma cell lines a whole chromosome 8 paint probe was used.

We investigated the functionality of the c-myc gene by detecting c-myc RNA expression with RT-PCR and c-myc protein by immunohistochemistry. 4/8 primary melanomas and 11/33 melanoma metastases showed additional c-myc signals relative to the centromere of chromosome 8 copy number. None of the nevi, safety margins or normal skin samples demonstrated this gain. In 2/7 melanoma cell lines (C32 and WM 266-4) isochromosome 8q formation with a relative gain of c-myc copies and a loss of 8p was observed. The highest c-myc gene expression compared to GAPDH was found in melanoma metastases (17.5%). Nevi (6.6%) and primary melanomas (5.0%) expressed the c-myc gene on a lower level. 72.7% of the patients with c-myc extra copies had visceral melanoma metastases (UICC IV), patients without c-myc gain in 35.0% only. The collective with additional c-myc copies also expressed the gene on a significantly higher level.

These results indicate that a c-myc gain in relation to the centromere 8 copy number might be associated with advanced cutaneous melanoma.


Mitotic cyclins and cyclin-dependent kinases in melanocytic lesions.

Tran TA, Ross JS, Carlson JA, Mihm MC Jr.

Department of Pathology and Laboratory Medicine, Albany Medical College and Samuel S. Stratton Veterans Administration Medical Center, NY 12208, USA.

Hum Pathol 1998 Oct;29(10):1085-90 Abstract quote

Recent evidence has implicated cyclins and cyclin-dependent kinases in the evolution and progression of various malignancies.

We studied the immunohistochemical expression of cyclin A, cyclin B, and cyclin-dependent kinase p34cdc2 in a broad spectrum of benign and malignant melanocytic lesions. Formalin-embedded, parrafin-fixed tissue sections from 66 malignant melanomas (MM) and 60 benign nevi were examined for the expression of these cell-cycle proteins. The results were compared with the standard proliferative marker Ki-67 and mitotic index. MM showed significantly higher immunoreactivity for cyclin A, cyclin B, p34cdc2, and Ki-67 compared with benign nevi. Cyclin A, p34cdc2, and Ki-67 displayed strong co-expression in MM. Overexpression of cyclin A and p34cdc2 correlated with histological type, mitotic activity, Ki-67 index, tumor thickness, Clark's level, and clinical outcome in MM.

In invasive MM, increased immunostaining of cyclin A and Ki-67 were associated with decreased patient survival. These findings indicate potential roles of mitotic cyclins and cyclin-dependent kinases in the pathogenesis and progression of malignant melanoma.


Relationship of tumorigenic malignant melanomas to dermal elastin: an expression of tumor/stromal interaction that may be related to prognosis.

Feinmesser M, Schachter JM, Tobar A, Sulkes J, Gutman H, Kruk N, Okon E.

Department of Pathology, Rabin Medical Center, Beilinson Campus, Petah Tiqva, Israel.

Am J Dermatopathol 2002 Apr;24(2):108-17 Abstract quote

Malignant melanomas, which produce a large number of substances active in connective tissue modulation, must contend with the dermis to grow and propagate.

We studied the morphologic interactions between tumorigenic malignant melanomas and dermal elastin. Formalin-fixed and paraffin-embedded tissues of 108 tumorigenic malignant melanomas were stained for elastic tissue with the Verhoeff-van Gieson method. Various aspects of the relationship between malignant melanoma and dermal elastin were analyzed in relation to the histologic and clinical data using univariate and multivariate analyses. Tumor thickness, mitotic rate, and the presence of elastin remnants within the tumors were found to be independent negative prognostic factors, the latter with borderline significance.

Tumors with more remnants of elastin were associated with higher stage of disease and lymph node and distant metastases. Tumor infiltration between the elastic fibers in the tumor depth was associated with high Clark level, greater tumor thickness, high stage of disease, and lymph node metastases. At least partial preservation of elastic fibers in the tumor depth was a relatively good prognostic factor whereas complete absence of elastin was an adverse factor. Focal or multifocal absence of elastin in the midst of the tumors or in their depth was usually associated with lymphocytic infiltrates.

We suggest that tumors with remnants of elastic fibers and/or invasion between elastic fibers in their depth may be fast growing and highly invasive. The absence of elastin within tumors and at their advancing edge may be related to the elaboration of elastin-degrading substances by melanoma cells or various inflammatory cells. Our findings indicate that the relationship between malignant melanomas and dermal connective tissue components, specifically elastin, may have prognostic significance.

m J Clin Pathol. 2007 Aug;128(2):260-4.Click here to read Links

Solar elastosis in cutaneous melanoma.

Department of Pathology, Veterans Affairs and Duke University Medical Centers, Durham, NC 27705, USA.


Am J Clin Pathol. 2007 Aug;128(2):260-4. Abstract quote

By studying more than 1,200 patients with cutaneous melanoma and long-term follow-up, I examined the relationship between solar elastosis and age at diagnosis of melanoma, key features of melanoma, and the outcome of overall survival in melanoma.

I found that melanomas with elastosis were diagnosed significantly later than those without elastosis (P approximately 0; log-rank test). This result may be because elastosis is positively related to age. However, I also found that melanomas of head and neck areas, which tend to have more elastosis, were diagnosed at later ages than melanomas of other body sites (P = 1.2 x 10-5; log-rank test). Thus, a second explanation for the results favors a protective effect of elastosis on the development of cutaneous melanoma, possibly related to increased levels of vitamin D.

I also found that once melanoma develops, cases with elastosis demonstrated no differences in thickness, mitotic rate, ulceration, or overall survival time from cases without elastosis.
Fatty acid synthase expression in cutaneous melanocytic neoplasms.

Kapur P, Rakheja D, Roy LC, Hoang MP.

1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mod Pathol. 2005 Aug;18(8):1107-12. Abstract quote  

Mammalian fatty acid synthase is a multifunctional enzyme complex involved in de novo synthesis of saturated fatty acids, and inhibitors of fatty acid synthase are being evaluated as potential therapeutic agents. Increased fatty acid synthase expression has been demonstrated in subsets of malignancies, including colon, breast, endometrium, prostate and ovarian carcinomas, and recently malignant melanomas.

We evaluated the immunohistochemical expression of fatty acid synthase in 155 cutaneous melanocytic lesions. They included 30 congenital nevi, 19 compound nevi, 40 Spitz nevi, 48 primary melanomas, and 18 metastatic melanomas. Fatty acid synthase expression was stronger in malignant melanomas in comparison to conventional nevi and Spitz nevi, and was the highest for metastatic melanoma. Of the primary malignant melanomas, mean fatty acid synthase scores were significantly greater for Clark levels IV and V compared to Clark levels I and II (P<0.001). In addition, melanomas with Breslow thickness 0.75-1.50 mm and >1.50 mm showed significantly higher mean fatty acid synthase scores compared with those with Breslow thickness <0.75 mm (P=0.013 and <0.001, respectively).

Of interest, congenital melanocytic nevi also showed strong fatty acid synthase expression, similar to that seen in metastatic melanoma. This may represent persistence of or regression to a fetal phenotype since normal fetal tissues are known to express high levels of fatty acid synthase.

Fatty acid synthase expression in melanoma.

Innocenzi D, Alo PL, Balzani A, Sebastiani V, Silipo V, La Torre G, Ricciardi G, Bosman C, Calvieri S.

Department of Dermatology, Institute of Experimental Medicine and Pathology, University of Rome 'La Sapienza', Italy, Department of Science and Society, University of Cassino, Italy.


J Cutan Pathol 2003 Jan;30(1):23-8 Abstract quote

Background: Fatty acid synthase (FAS), the key enzyme responsible for the synthesis of fatty acids, is weakly expressed in some normal human tissues. Recently, FAS has been demonstrated to be overexpressed in many non-neoplastic highly proliferative lesions and in aggressive carcinomas with poor outcome, including colon, breast and ovary carcinomas.

Methods: In order to evaluate the prognostic significance of FAS in human melanoma, we analysed by means of immunohistochemistry, using a monoclonal anti-FAS antibody, 77 primary melanomas and 30 nodal and cutaneous metastasis. Thirty nevi (15 dermal and 15 junctional nevi) were used as controls. All patients were followed-up for 5 years.

Results: Thirty-four melanomas expressed strong FAS immunostaining; the remaining 43 cases showed weak expression or were negative. All cutaneous and nodal metastasis were strongly positive. All patients with metastases deceased during the follow up period. Control specimens expressed weak staining. None of these patients developed recurrence. Statistical analysis revealed significant association of FAS expression with Breslow thickness (p = 0.012). The intensity of FAS immunostaining was also predictive of prognosis (p = 0.049).

Conclusions: FAS is a reliable prognostic marker in human melanomas. FAS predictive strength is increased when associated with Breslow thickness. The observation of FAS in human melanomas may stratify patients for stricter follow-ups and suggest different therapeutic approaches.


Epithelioid cell melanomas have greater DNA ploidy abnormalities than spindle cell melanomas: cytological evidence for a higher malignant potential of the former.

Chi HI, Uyeda Y, Umebayashi Y, Otsuka F.

Department of Dermatology, Tokyo Hitachi Hospital, Japan.

Arch Dermatol Res 1993;285(7):410-4 Abstract quote

The cellular DNA ploidy of 30 cases of malignant melanoma was measured by 4',6-diamidino-2-phenylindole-DNA (DAPI-DNA) microfluorometry.

DNA histograms and DNA index values were compared among melanomas of different cell morphology. Epithelioid cell melanomas often showed greater DNA aneuploidy than spindle cell melanomas in terms of histographic pattern. DNA index values of the former (mean +/- standard error, 1.84 +/- 0.31) were significantly higher than those of the latter (1.55 +/- 0.24; P < 0.05). The DNA index values of mixed-type melanomas were intermediate. These results indicate that the epithelioid cell melanomas have greater DNA ploidy abnormalities which are usually correlated with a greater malignant potential in pigmentary neoplasms.

Thus our results confirm clinical evidence that melanoma patients with the epithelioid type of cells have a poorer prognosis than those with the spindle type of cells.


Does biopsy type influence survival in clinical stage I cutaneous melanoma?

Lederman JS, Sober AJ.

J Am Acad Dermatol 1985 Dec;13(6):983-7 Abstract quote

A total of 472 patients with clinical Stage I cutaneous melanoma were analyzed to determine influence of type of diagnostic biopsy on survival. Of these patients, 119 had had an incisional biopsy (either punch or incision) and 353 had an excisional biopsy. Patients were grouped by thickness category and outcome compared between the biopsy types.

Within each thickness category, there is no statistically significant difference in survival between the two groups. The observation that none of the seventy-six patients with primary tumors less than 1.70 mm have died following incisional biopsy strongly argues against any deleterious effect of incisional biopsy in this group. Alternatively, if the two highest-risk groups (greater than or equal to 1.70 mm) are analyzed as a single group, an adverse effect is seen in the incisional biopsy group (p less than 0.05). However, when the data from these groups are subjected to multivariate analysis, biopsy type is not a significant factor in the model.

This study shows that either biopsy method may be used in first evaluating patients with suspected melanoma.

Does wide excision as the initial diagnostic procedure improve prognosis in patients with cutaneous melanoma?

Lederman JS, Sober AJ.

J Dermatol Surg Oncol 1986 Jul;12(7):697-9 Abstract quote

502 patients with clinical stage I cutaneous melanoma were reviewed to determine if performing a wide excision (4-5 cm) at the time when the diagnosis of melanoma is suspected, improves the survival.

Patients were divided into two groups based on initial biopsy type and thickness category. Group 1, wide excision; group 2, total excision with narrow margins, incisional, or punch biopsies. There was no evidence that patients who had had a diagnostic and therapeutic procedure (wide excision) as the initial approach had a better survival than those who had had another form of biopsy before definitive surgery.

We cannot recommend excision with wide margins as the initial biopsy procedure for a lesion suspected to be melanoma before histologic verification, since it does not increase survival for melanoma and may result in unnecessary aggressive surgery in the case of a misdiagnosed benign lesion.

Effect of initial biopsy procedure on prognosis in Stage 1 invasive cutaneous malignant melanoma: review of 1086 patients.

Lees VC, Briggs JC.

Department of Plastic Surgery, Addenbrooke's Hospital, Cambridge, UK.

Br J Surg 1991 Sep;78(9):1108-10 Abstract quote

After treatment for primary clinical Stage 1 invasive cutaneous malignant melanoma, 1086 patients were followed for a minimum of 5 years from initial operation. Patient data were retrieved from the unit's melanoma registry; 96 (8.8 per cent) were treated initially by incisional biopsy, 292 (26.9 per cent) by narrow margin excision biopsy and 698 (64.3 per cent) by wide margin excision.

Logistic regression analysis was performed to assess the statistical significance of the association between the various factors. The method of initial biopsy was related to maximal tumour thickness, age, and sex.

Incisional biopsy rendered 38 out of 96 (40 per cent) lesions not fully assessable on current histopathological criteria, significantly higher than for the other biopsy techniques (P less than 0.0001). Incisional biopsy did not adversely affect prognosis in terms of local recurrence and mortality. Prognosis was related to tumour thickness, age and sex of the patient, and not to biopsy technique.

We recommend that all suspicious lesions should be submitted to excisional rather than incisional biopsy to avoid compromising the histological assessment, given the importance of maximal tumour thickness in determining treatment and prognosis.

Influence of biopsy on the prognosis of cutaneous melanoma of the head and neck.

Austin JR, Byers RM, Brown WD, Wolf P.

Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, USA.

Head Neck 1996 Mar-Apr;18(2):107-17 Abstract quote

BACKGROUND: This study was performed to determine the effect of biopsy type on survival rates and on local, regional, and distant metastasis in patients with head and neck cutaneous melanoma.

METHODS: A case series of 159 patients with melanoma of the head and neck referred to a tertiary-care center between 1983 and 1991, with a median follow-up of 38 months, was reviewed. Information analyzed included patient's age, sex, type of treatment, mode of biopsy, presence of residual melanoma in reexcision, location of lesion, presence of ulceration, Clark's level, Breslow thickness, and histologic type of the melanoma.

RESULTS: Excisional biopsy was performed in 79 patients, incisional biopsy in 48, and other procedures (shave, needle biopsy, cauterization, or cryotherapy) in 32. There were no significant pretreatment differences among the three groups in sex, thickness, histologic type, presence of nodal disease, or type of treatment. Pretreatment location of lesion was significantly different (p = .03) between the excisional and other biopsy types. Association between type of biopsy and survival rate was significant (p<.001):31.3% of patients in the incisional biopsy group died of disease, as did 25% of the other biopsy group, versus 8.9% of the excisional biopsy group; 31.3% of patients in the incisional biopsy group developed distant metastases, as did 28.1% of the other biopsy type, versus 10.1% of those in the excisional biopsy group (p = .01). There was no significant difference in local p = .37) or regional (p = 1.00) recurrence among the three biopsy groups. Multivariate analysis showed presence of tumor in the re-excision specimen, biopsy type, and nodal disease to be independent prognostic factors.

CONCLUSIONS: Our study suggests that the type of biopsy of cutaneous melanoma of the head and neck may influence the clinical outcome.

Incisional biopsy and melanoma prognosis.

Bong JL, Herd RM, Hunter JA.

Departments of Dermatology, Western Infirmary, Glasgow, and The Royal Infirmary of Edinburgh.

J Am Acad Dermatol 2002 May;46(5 Pt 1):690-4 Abstract quote

BACKGROUND: There are many circumstances in clinical practice in which it is helpful to have a definitive diagnosis of melanoma before subjecting a patient to mutilating surgery. Previous studies on the effect of incisional biopsy on melanoma prognosis were conflicting and lacked a matched control group to account for the other prognostic indicators.

OBJECTIVE: We set up this study to investigate the effect of incisional biopsy on melanoma prognosis.

METHODS: The design was of a retrospective case control. Data were obtained from the database of the Scottish Melanoma Group; the database was set up in 1979 to collect detailed clinical, pathologic, and follow-up data on all patients diagnosed with melanoma in Scotland. Each incisional case was matched against 2 excision cases controlling for age, sex, sites, and Breslow thickness. The main outcome measures were time from initial biopsy to recurrence and to melanoma-related death.

RESULTS: Two hundred sixty-five patients who had incisional biopsy before definitive excision of melanoma were included in the study; these were matched with 496 cases of excisional biopsy specimens. Cox's proportional hazard model for survival analysis showed that biopsy type had no significant effect on recurrence (P =.30) or melanoma-related death (P =.34).

CONCLUSIONS: This study is the largest series on the effect of incisional biopsy on melanoma prognosis to date and the first to include matched controls. Melanoma prognosis is not influenced by incisional biopsy,. before definitive excision.



Correlation between KIT expression and KIT mutation in melanoma: a study of 173 cases with emphasis on the acral-lentiginous/mucosal type

Carlos A Torres-Cabala1,2, Wei-Lien Wang1, Jonathan Trent3, Dan Yang1, Su Chen1, John Galbincea1, Kevin B Kim3, Scott Woodman3, Michael Davies3, Jose A Plaza1, J W Nash1, Victor G Prieto1,2, Alexander J Lazar1,2 and Doina Ivan1,2

1Department of Pathology, The University of Texas—MD Anderson Cancer Center, Houston, TX, USA
2Department of Dermatology, The University of Texas—MD Anderson Cancer Center, Houston, TX, USA
3Department of Melanoma Medical Oncology, The University of Texas—MD Anderson Cancer Center, Houston, TX, USA
Correspondence: Dr CA Torres-Cabala, MD, Departments of Pathology and Dermatology, The University of Texas—MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit no. 85, Houston, TX 77030-4009, USA.

Modern Pathology (2009) 22, 1446–1456

The role of immunohistochemistry in the assessment of KIT status in melanomas, especially acral lentiginous/mucosal, is not well established. Although the reported prevalence of KIT mutations in acral lentiginous/mucosal melanomas is relatively low, detection of mutations in KIT can have profound therapeutic implications.

We evaluated the efficacy of immunohistochemistry to predict mutations in KIT. One hundred seventy-three tumors, comprising primary and metastatic melanomas (141 acral lentiginous/mucosal, 5 nodular, 4 lentigo maligna, 3 superficial spreading, 2 uveal, 1 melanoma of soft parts, 8 metastases from unclassified primaries, and 9 metastases from unknown primaries) were studied. Immunohistochemical expression of KIT using an anti-CD117 antibody and KIT mutational analysis by gene sequencing of exons 11, 13, and 17 were performed.

Eighty-one percent of acral lentiginous/mucosal melanomas, primary and metastatic, showed KIT expression by at least 5% of the tumor cells. The overall frequency of activating KIT gene mutations in acral lentiginous/mucosal melanomas was 15% (14 out of 91 cases), being the L576P mutation in exon 11 the most frequently detected (4 of 14 cases). Cases showing less than 10% positive tumor cells were negative for KIT mutations. Eighty-two percent (12 of 14) of cases positive for KIT mutation showed KIT expression in more than 50% of the cells. An association between immunohistochemical expression of KIT and mutation status was found (P=0.007).

Immunohistochemical expression of KIT in less than 10% of the cells of the invasive component of acral lentiginous/mucosal melanomas appears to be a strong negative predictor of KIT mutation and therefore can potentially be used to triage cases for additional KIT genotyping.

Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes.

Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A, Jahnke K, Hauschild A, Hirakawa S, Mihm MC, Detmar M.

[1] 1Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [2] 2Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Mod Pathol. 2005 Sep;18(9):1232-42. Abstract quote  

Cutaneous melanoma is a common melanocytic neoplasm that can quickly metastasize to regional lymph nodes. Currently, prognosis is determined by measuring tumor thickness but more reliable markers for metastatic spread are urgently needed.

We investigated whether the extent of tumor lymphangiogenesis can predict melanoma metastasis to sentinel lymph nodes. We quantified the extent of tumor lymphangiogenesis, as well as other factors, in excised primary tumors and in sentinel lymph node biopsy samples from 45 patients with primary cutaneous melanoma. The results were correlated with histological and clinical outcome.

Primary melanomas from patients whose tumors had metastasized to the sentinel lymph nodes contained prominent 'hot spots' of increased lymphatic vessel density, compared to nonmetastatic tumors. Multivariate risk analysis revealed that the lymphatic vascular area of primary melanomas, an index of tumor lymphangiogenesis, was the most sensitive prognostic marker for sentinel lymph node metastasis, and was even able to more accurately predict which tumors were metastatic to sentinel lymph nodes than the currently used method of measuring tumor thickness. Highly lymphangiogenic melanomas maintained their lymphangiogenic activity after metastasis to the sentinel lymph node. The extent of tumor lymphangiogenesis is a highly sensitive (83%) and specific (89%) prognostic marker of lymph node metastasis.

Assessment of lymphangiogenesis in primary melanomas may be a more effective approach than the currently used technique of measuring tumor thickness in selecting patients with early metastatic disease for aggressive therapy.
  Arch Dermatolo 2008;144:462-467
Ki-67 (MIB-1)

J Cutan Pathol 1991;18:264-72.
J Cutan Pathol 1992;19:110-5.
J Invest Dermatol 1995;105:22-6.
J Am Acad Dermatol 1996;35:416-8.

Significance of cell kinetic parameters in the prognosis of malignant melanoma: a review.

Department of Dermatology, Erasme University Hospital, Brussels, Belgium.

J Cutan Pathol. 2007 Feb;34(2):139-45. Abstract quote

Malignant melanoma has been extensively studied concerning methods of predicting progression and clinical outcome. The maximum tumor thickness as measured by Breslow's method is the cornerstone prognostic criterion, but despite this, evolution of the disease in some patients remains unpredictable, confirming that new reliable prognostic factors are awaited.

Cell kinetic evaluation has been shown to be a useful tool for assessing the prognosis of breast and gastrointestinal cancer patients. Indeed, in these fields, the mitotic index and MIB-1 expression index, which are indirect estimates of the growth fraction of tumor cell population, are commonly shown to correlate with tumor grade and patient survival and presented as prognostic factors.

In melanoma, results of cell kinetic investigations are conflicting: some studies have established a link between high proliferative activity and a bad prognosis, whereas other reports suggest the opposite. The aim of this review is to discuss these findings.

Concurrent Ki-67 and p53 immunolabeling in cutaneous melanocytic neoplasms: an adjunct for recognition of the vertical growth phase in malignant melanomas?

Kaleem Z, Lind AC, Humphrey PA, Sueper RH, Swanson PE, Ritter JH, Wick MR. Lauren V.

Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, Missouri, USA.

Mod Pathol 2000 Mar;13(3):217-22 Abstract quote

Ki-67 labeling of paraffin sections has been correlated with the number of cells in non-G(o) phases of the replicative cell cycle, and this immunohistochemical technique has been applied to the evaluation of a variety of human neoplasms. Similarly, immunolabeling for p53 protein has been used to detect mutations in the corresponding gene, as a reflection of possible cellular transformation in the same context.

Both of these techniques were applied to 253 melanocytic tumors of the skin to assess their possible utility in the diagnosis and subcategorization of such lesions. They included 76 banal (common) nevi (CN), 39 Spitz nevi (SN), 62 superficial spreading malignant melanomas in radial growth (SSMMs), 32 nodular malignant melanomas (NMMs), 21 lentigo maligna melanomas in radial growth (LMMs), and 23 melanomas arising in association with preexisting compound nevi (MCN). One hundred cells were counted randomly in each tumor, and dark, exclusively nuclear reactivity was scored as positive labeling; results were recorded as percentages.

Negligible Ki-67 and p53 labeling was seen in CN and SN, at a level that was similar to that obtained in cases of LMM and MCN. T

he largest proportion of Ki-67-positive and p53-positive cells was observed in NMMs, followed by SSMMs. Radial growth-phase SSMMs and LMMs demonstrated immunoprofiles that were similar to those of melanocytic nevi, and MCN did so as well.

The prototypical malignant melanocytic tumor representing the vertical growth phase-nodular melanoma--demonstrated a statistically significant difference from all other lesions in this study with respect to Ki-67 index (P = .008, chi2) and p53 reactivity (P < .000001, chi2). Subsequent concurrent use of a Ki-67 threshold index of 10% and a p53 index of 5% correctly indicated the presence of vertical growth in 75% of NMMs, whereas only 8% of radial growth phase melanomas of other types were colabeled at the same levels of reactivity for the two markers (P < .00001, chi2).

Thus, although the distinction between benign and malignant melanocytic tumors could and should not be based on immunohistology for Ki-67 and p53, these results suggest that the latter determinants may, in fact, be used as an adjunct to morphology in the recognition of the vertical growth phase in cutaneous malignant melanomas.

J Am Acad Dermatol 2001;44:188-92

Ki-67 reactivity in primary melanomas was evaluated as at least 5% of positive neoplastic cells and was assessed on fresh specimens of 55 primary lesions at the time of excision

At least 4 fields of approximately 100 tumor cells each per slide were counted at 40 magnification. The number of Ki-67-reactive cells in each field was determined as a percentage of the total number of tumor cells counted. A mean percentage of Ki-67 immunoreactive melanoma cells was calculated for each lesion. The percentage of positive cells per lesion was scored according to 3 different categories: zero to 4%, 5% to 10%, 11% to 30%. A cut-off point of 5% stained cells was chosen to identify positive lesions.

Reactivity was correlated with metastatic relapse of patients in a prospective study, by means of multivariate Cox regression models (follow-up, 3-120 months)

Ki-67 immunoreactivity was associated with increasing thickness (P = .003)
Positive correlation was found between Ki-67 reactivity and metastatic dissemination in primary melanomas less than 1.5 mm thick (n = 23; mean thickness, 0.75 0.3 mm; P = .002)

A negative correlation was found between Ki-67 reactivity and metastatic activity in primary melanomas thicker than 1.5 mm (n = 32; mean thickness, 4.0 1.6 mm; P = .019).

Ki-67 proliferative activity appears to be a possible predictor of metastasis in primary melanomas, in particular, an indicator of poor prognosis in lesions less than 1.5 mm thick.


Am J Dermatopathol 2001;22:489-495

Average number and maximal number (%) of MIB-1 positive nuclei were determined in superficial, middle, and deep dermal zones as well as the entire lesion

23 compound nevi
17 dysplastic nevi
8 Spitz nevi
24 malignant melanomas

Utilizing the % MIB-1 mean and max from whole lesions had better discriminating abilities than individual zones

Using the % Mean from all zones, all lesions except one Spitz nevus and 3 melanomsa could be correctly classified as benign or malignant

Using the % MIB-1-max from all zones, all lesions but 2 Spitz nevi could be correctly classified

A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions.

Li LX, Crotty KA, McCarthy SW, Palmer AA, Kril JJ.

Department of Pathology, University of Sydney, and Centre for Education and Research on Ageing, Concord Hospital, New South Wales, Australia.

Am J Dermatopathol 2000 Dec;22(6):489-95 Abstract quote

Differentiation between malignant melanomas and benign nevi can sometimes be difficult by conventional histopathology, and additional diagnostic markers may be helpful.

This study investigated the immunoreactivity of the cell proliferation marker MIB1-Ki67 in 23 compound nevi, 17 dysplastic nevi, 8 Spitz nevi (SN), and 24 malignant melanomas (MMs) and evaluated its ability in separating benign nevi from MMs.

In each lesion, the average number (percentage) of MIB1-positive nuclei (%MIB1-Mean) and the maximal number (percentage) of MIB1-positive nuclei (%MIB1-Max) were determined from each of the superficial, middle, and deep dermal zones of the lesion as well as from the entire lesion. The %MIB1-Max was determined from subjectively selected area(s) of high count. Malignant melanomas had a significantly greater %MIB1-Mean and %MIB1-Max than all benign nevi in all individual zones and in the entire lesion (p < 0.05). Discriminant analysis showed that the %MIB1-Mean and %MIB1-Max counted from the whole lesions had better discriminating abilities than from the individual zones. By using the %MIB1-Mean from all zones, all lesions except 1 SN and 3 MMs could be correctly classified as benign or malignant. When using the %MIB1-Max from all zones, all but 2 SN could be correctly separated as benign or malignant.

Thus, MIB1-Ki67 immunoreactivity closely correlates with the benignancy or malignancy of melanocytic lesions and may assist in the differentiation of benign nevi from MMs.

MIB-1 monoclonal antibody to determine proliferative activity of Ki-67 antigen as an adjunct to the histopathologic differential diagnosis of Spitz nevi

J Am Acad Dermatol 2001;44:500-4 Abstract quote

Twenty-five compound SNs, 27 MMs, and 26 compound nondysplastic melanocytic nevi (MNs) were immunostained with the MIB-1 antibody.

Results: The mean counts of MIB-1-stained tumor cells of the epidermal and dermal components, both alone and together, were significantly lower in SNs and MNs than in MMs (P < .0001). The dermal counts showed the best discriminating power. In addition, the mean dermal/epidermal count ratios for MIB-1 in SNs and MNs (0.25 and 0.23, respectively) were significantly lower than the corresponding ratio (0.94) in MMs (P < .0001).

Conclusion: MIB-1-stained tumor cell counts, especially of the dermal component, and dermal/epidermal MIB-1 count ratios may be helpful as an adjunct to the histopathologic differential diagnosis of SN.


Cutaneous malignant melanoma: correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor.

Toth-Jakatics R, Jimi S, Takebayashi S, Kawamoto N.

Second Department of Pathology, Fukuoka University, School of Medicine, Japan.

Hum Pathol 2000 Aug;31(8):955-60 Abstract quote

To investigate the possible role of mast cells (MC) in the angiogenic process in cutaneous melanoma, we examined tissue samples from 35 adult patients with primary malignant melanoma and compared with 20 intradermal benign nevi.

MC were identified by anti-tryptase, microvessels by anti-CD34, and vascular endothelial growth factor (VEGF) expression by standard immunohistochemical methods. Tryptase-positive MC expressing VEGF were identified by double immunostaining. The numbers of MC and microvessels around the tumor were determined by the point counting method. MC density was significantly greater in melanoma compared with benign nevi (197.6 +/- 19.4 v 95.7 +/- 5.0/mm2, P < .001). Vascular density was also significantly higher in melanoma than in benign lesions (3.6-fold, P < .001). Double immunostaining showed the presence of VEGF in the cytoplasm of tryptase-positive peritumoral MC. The percentage of this MC-subtype was significantly higher in melanoma than in nevus tissues (71.9 +/- 2.4% v 30.6 +/- 2.5%, P < .001). A strong significant correlation was shown between the number of VEGF+ MC and microvessel density (r = .811, P < .001). MC count and VEGF+ MC count, as well as microvessel density were significantly higher in aggressive (metastasizing) melanomas (P < .001).

Our results suggest that peritumoral accumulation of MC and the subsequent release of potent angiogenic factor such as VEGF may thus represent a tumor-host interaction that may favor progression of this tumor.


Am J Dermatopathol 2001;23:29-35

Tumors of 44 patients
25/44 positive (nuclear and/or cytoplasmic staining positivity)
37.5% of level I-III positive
80% of level IV-V positive

Strong correlation between expression and level of invasion and tumor thickness
Survival distribution function curve (Kaplan-Meier) had a better survival rate for negative group


Early detection of asymptomatic pulmonary melanoma metastases by routine chest radiographs is not associated with improved survival.

Tsao H, Feldman M, Fullerton JE, Sober AJ, Rosenthal D, Goggins W.

Department of Dermatology, MGH Melanoma Center, Massachusetts General Hospital, Boston 02114, USA.
Arch Dermatol. 2004 Jan;140(1):67-70. Abstract quote  

OBJECTIVE: To determine if earlier detection of pulmonary metastasis by routine chest radiography (CR) is associated with a prolonged survival.

DESIGN: A computer-assisted search of all CR reports on patients with melanoma between 1990 and 1994 at the Massachusetts General Hospital, Boston. Positive or suspicious findings for pulmonary metastasis were further pursued through review of medical records and tumor registry files.

SETTING AND PATIENTS: A hospital-based population of patients with melanoma undergoing routine CR at Massachusetts General Hospital.

RESULTS: Overall, of 994 patients, 75 were identified as having pulmonary metastases by CR (1937 total chest radiographs). In addition, there were 63 patients with suspicious findings that were later shown to be false positive. Chest radiographs provided the initial evidence of metastases in 41 asymptomatic individuals. Thirty-four patients had known melanoma metastases to other sites at the time of the first abnormal chest radiograph. Survival after identification of pulmonary metastasis did not differ significantly between the 2 groups.

CONCLUSIONS: In this study, there was no evidence to support the notion that earlier detection of pulmonary metastasis in otherwise asymptomatic individuals confers a survival advantage in an unselected melanoma population.

Metastasis of cutaneous malignant melanoma to angiolipoma: the tumor-to-tumor metastasis phenomenon.

Alonso S, Rodriguez-Peralto JL, Perez-Espejo G.

Department of Pathology, '12 de Octubre' University Hospital, Madrid, Spain.

J Cutan Pathol. 2003 May;30(5):323-5. Abstract quote

BACKGROUND: Although the phenomenon of tumor-to tumor metastasis is not rare, it has been reported in only eight cases with malignant melanoma as the primary tumor.

METHODS: This case describes a patient with cutaneous malignant melanoma that metastasized to an angiolipoma. To our knowledge this is the second case of a malignant melanoma metastasizing to another primary cutaneous tumor and the first to do so in a lipoma.

CONCLUSION: In this report we present the clinical and histopathologic features of this special case and review the relevant literature.

Desmoplastic Melanomas

World J Surg 1992;16:186-90.

Series of 58 patients, 17 patients were noted to have local recurrence with the primary site of involvement on the head and neck
Eleven of these patients progressed to wider dissemination
No relationship between the site and histologic pattern of the primary lesion in those patients with lymph node metastasis

Elective lymphadenectomy was performed in 6 patients, all of whom had negative pathology
For those who had visceral disease, the major sites of involvement were liver, bone, brain, lung, spine, para-aortic nodes, and general dissemination

Melanomas with predominant neurotropism had a low incidence of visceral metastasis
However, those with evidence of neural transformation (ie, tumors that develop a neural appearance) without neurotropism appeared to have a high incidence of local recurrence and the potential for visceral recurrence rather than perineural and intraneural invasion

Rate of lymph node metastases of 14% appears to be lower compared with 37% for nondesmoplastic melanomas

Patients with a median tumor thickness of 6.5 mm (range, 2.15-11 mm) had lymph node recurrence, visceral recurrence, or cranial nerve neuropathies, whereas those without systemic recurrence had a median thickness of 3.6 mm (range, 0.45-16 mm)


Ann Surg 1981;194:108-112

Defined as discrete nests of melanoma cells that are noncontiguous and clearly separated from the main body of tumor by normal reticular dermal collagen or subcutaneous fat and are detected histologically

Overall, prognosis of patients is similar to that of patients with macrosatellites and should be categorized as stage III

Melanoma metastatic to "lipomata".

Mann BD, Finck SJ, Cohchran AJ, Morton DL.

J Surg Oncol 1984 Feb;25(2):98-9 Abstract quote

Three patients presented with solitary melanoma metastases that mimicked a simple "lipomata." On further investigation each patient had a discrete fatty tissue tumor mass surrounding a melanoma metastasis.

The presence of an enlarging mass in patients with a history of melanoma should be viewed with suspicion and a biopsy should be performed.


Cancer 1984;53:2183-2187

Presence of microsatellites is highly correlated with occult regional lymph node metastases in multivariate analysis


Arch Surg 1991;126:1461-1468

Compared with matched controls, microsatellite patients had a significantly decreased disease-free survival (27% versus 60% at 10 years) and decreased overall survival (37% versus 65% at 10 years)

5 YRS was 36% for patients with microsatellites versus 89% for patients without

Chromogenic in situ hybridization analysis of melastatin mRNA expression in melanomas from American Joint Committee on Cancer stage I and II patients with recurrent melanoma.

Johns Hopkins Hospital, Baltimore, MD, USA.


J Cutan Pathol. 2006 Sep;33(9):599-607. Abstract quote

Objective: To determine whether loss of melastatin (MLSN) is a universal phenomenon in American Joint Committee on Cancer (AJCC) stage I and II melanoma patients who experienced recurrence.

Material and methods: Paraffin blocks of primary melanomas (PMs) were retrieved from 30 patients who had a negative sentinel lymph node biopsy and developed recurrent melanoma (AJCC stage I and II). Chromogenic in situ hybridization (CISH) methods were utilized to evaluate the expression of MLSN mRNA. These results were correlated with clinicopathologic data.

Results: Variable, heterogeneous expression of MLSN mRNA was identified in normal, in situ and invasive melanocytes within and between cases. For the invasive PM component, 24 (80%) had focal, regional or complete loss of MLSN mRNA. The remaining 20% had either regional or total partial downregulation of MLSN mRNA. Intact MLSN mRNA expression was present regionally in 14/30 (47%), with mean relative tumor area of 38%, range 5-85%. Increasing loss of MLSN mRNA significantly correlated with increasing tumor depth and microsatellites (r = 0.1/0.4, p = 0.04). However, thin, AJCC T stage 1a PM had higher relative mean loss than intermediate AJCC T stage 2a/2b/3a thickness PM (65% vs. 34%/48%/25%). Increasing loss of MLSN mRNA significantly impacted on disease free survival (DFS) by multivariate analysis (58 vs. 0% 2 years DFS, </= 75 vs. >75% mRNA loss, p = 0.02). Decreased overall survival significantly correlated with increasing age and vascular invasion on multivariate analysis.

Conclusion: Extensive loss of MLSN in PM correlated with aggressive metastatic melanoma. Ancillary testing for MLSN mRNA expression by CISH could offer a means to more accurately identify AJCC stage I and II patients at risk for metastatic disease, who could benefit from adjuvant therapy.

Hum Pathol 2000;31:1346-1356
Inverse correlation with metastatic potential in human and murine cell lines, this study examined archived specimens

Study utilized in situ hybridization with S35 labeled probes, mRNA expression was analyzed in 64 cases of normal skin, benign melanocytic nevi, primary cutaneous melanoma, and melanoma metastases

Ubiquitous expression was observed in all benign nevi (14/14) with some nevi showing a gradient of reduced expression with increased dermal depth
Uniform expression in 49% of primary cutaneous melanoma (18/37)
Loss of expression in 53% (19/36) of invasive melanoma
Loss of expression in 100% of melanoma metastases (11/11)

Focal aggregate or nodule of melanoma cells without detectable signal was the most commonly observed pattern in melastatin loss of expression

The role of microsatellites as a prognostic factor in primary malignant melanoma.

Shaikh L, Sagebiel RW, Ferreira CM, Nosrati M, Miller JR 3rd, Kashani-Sabet M.

Melanoma Center, Cutaneous Oncology Program, Cancer Center, University of California, San Francisco, CA 94115, USA.

Arch Dermatol. 2005 Jun;141(6):739-42. Abstract quote  

OBJECTIVE: To determine the impact of microsatellites as a prognostic factor in primary cutaneous melanoma.

DESIGN: Retrospective cohort study.

SETTING: Tertiary referral center.Patients A total of 504 patients with a history of primary melanoma observed for 2 years or having experienced a first relapse.

MAIN OUTCOME MEASURES: Overall survival (OS) and relapse-free survival (RFS).

RESULTS: Forty-five patients had evidence of microsatellites in their primary melanoma. Presence of microsatellites significantly correlated with the presence of several other histologic high-risk factors such as tumor thickness, ulceration, Clark level, vascular factors, and mitotic rate. Univariate analysis demonstrated decreased RFS and OS in patients with microsatellites. Presence of microsatellites was associated with increased locoregional metastasis but not distant metastasis. In multivariate analysis, with the inclusion of 6 other clinical and histologic factors, presence of microsatellites was a significant predictor of RFS but not OS. Patients with clinical macrosatellites had a trend toward worsening OS compared with those with microsatellites.

CONCLUSIONS: The presence of microsatellites is intimately tied to other markers of melanoma aggressiveness. Microsatellites appear to predict locoregional relapse and RFS but neither distant metastasis nor OS. These results may have implications for patient care as well as the inclusion of microsatellites in stage III of the current classification.
The importance of mitotic rate as a prognostic factor for localized cutaneous melanoma.

Barnhill RL, Katzen J, Spatz A, Fine J, Berwick M.

Department of Dermatology, George Washington University Medical Center, Washington, DC, USA.

J Cutan Pathol. 2005 Apr;32(4):268-73. Abstract quote  

Background: Tumor ulceration (TU) is considered the second most important prognostic factor after Breslow thickness for localized cutaneous malignant melanoma (CMM). However, many studies have not included mitotic rate (MR) with TU in these analyses. When both TU and MR are included in the same analysis, MR appears to be the more important than TU and TU loses its significance as an independent prognostic factor.

Methods: The relative importance of TU and MR as prognostic factors in localized CMM were compared in a population-based series of 650 consecutive invasive CMM cases ascertained from the Connecticut tumor registry and reviewed by a single dermatopathologist (RLB), during the period between January 15, 1987 and May 15, 1989. Seventeen clinical and histopathological variables including tumor thickness measured in mm, TU recorded as present or absent, and MR recorded as number per mm(2) were included in an unconditional logistic regression model and selected for inclusion using a backward stepwise algorithm with death as an endpoint or at least five-years follow-up.

Results: In the multivariate regression, the independent prognostic factors included: 1. tumor thickness in millimeters (OR = 1.5, 95% CI = 1.3-1.9) 2. moderate mitotic index (between 1 and 6): (OR = 8.3, 95% CI 2.4-28.7), 3. mitotic index (>6): (OR = 11.6, 95% CI = 3.0-44.6), 4. solar elastosis: (inversely associated with mortality)(OR = 0.4, 95% CI = 0.2-8). After adjustment for MR, TU lost its significance. When MR was left out of the analysis, ulceration then became an independent prognostic factor. The model with ulceration only (excluding MR) showed a relative risk (RR) of 2.4 (95%CI: 1.1-5.1). In the model with MR only, MR had a RR of 14.5 (95% CI3.9-53.7). Finally, regression analysis including both TU and MR yielded an RR of 11.6 for MR and 1.7 for TU.

Conclusions: Our results suggest that MR as a proxy for tumor proliferation is a more important prognostic factor than TU.

Melanoma growth stimulatory activity in primary malignant melanoma: prognostic significance.

Middleman BR, Friedman M, Lawson DH, DeRose PB, Cohen C.

Emory University School of Medicine, Atlanta, Georgia.

Mod Pathol 2002 May;15(5):532-7 Abstract quote

Malignant melanoma (MM) cells do not require all exogenous growth factors of normal melanocytes. It is hypothesized that they make their own growth factors including melanoma growth stimulatory activity (MGSA). Cultured melanoma cells respond to MGSA with increased growth and angiogenesis suggesting a role for MGSA in MM proliferation, differentiation, and progression.

We assessed the prognostic significance of MGSA expression in 37 primary MM immunostained for MGSA. Immunostains were graded for intensity (0-3+), percentage of cells immunostained, and location of immunostain (intraepidermal, junctional, or dermal). In addition, 31 melanocytic and 23 dysplastic nevi were similarly studied for MGSA expression. All MM showed the presence of immunostain, 6 (16%) 1+, 12 (32%) 2+, and 19 (51%) 3+. Six (16%) had immunostain in </=50% tumor cells, 31 (84%) in >50%. A significant number of MM showed >50% tumor cells staining at the dermal-epidermal junction compared with intraepidermal staining (P <.0001). Intensity and amount of immunostain did not correlate with Clark's or Breslow's level. During a mean follow-up of 60 months (range: 5-101) on 27 patients, there were 4 local recurrences, 6 distant metastases, and 10 deaths. MGSA expression was not of prognostic significance with regard to survival (overall, disease free), or local recurrence or distant metastasis in primary MM. MGSA expression was similar in benign melanocytic and dysplastic nevi. Strong diffuse expression was noted in the junctional component of all junctional and most compound nevi.

The dermal component consistently expressed less or no (in 45% of intradermal nevi) MGSA. MGSA expression does not correlate with prognosis in MM. Increased expression of MGSA at the dermal-epidermal junction in nevi and MM may indicate a role for MGSA in early local growth, before development of atypia.


Enhanced survival in patients with multiple primary melanoma.

Doubrovsky A, Menzies SW.

Sydney Melanoma Unit, Melanoma and Skin Cancer Research Institute, Department of Surgery, University of Sydney, Sydney, Australia.

Arch Dermatol. 2003 Aug;139(8):1013-8. Abstract quote

OBJECTIVE: To calculate survival probabilities of patients with 3 or more multiple primary melanomas.

DESIGN: Retrospective cohort study of patients with primary melanoma.

SETTING: Patients treated at a tertiary center (Sydney Melanoma Unit, Sydney, Australia) for stage I or II melanoma between 1983 and 1999.Patients From 5250 patients with primary melanoma, 264 (5.0%) had double and 34 (0.6%) had 3 or more primary melanoma lesions.

RESULTS: The estimated 10-year risk for developing a second primary melanoma in these patients was 12.7% (95% confidence interval [CI], 10.5%-14.9%). For those patients who had 2 primary melanomas, the estimated 10-year risk of developing a third lesion was 27.7% (95% CI, 14.7%-36.7%). When controlling for known prognostic factors in a proportional hazards regression model, the number of primary melanomas was a significant favorable survival predictor when the thickest or the first tumor was modeled. In patients with 3 or more primary melanomas, 31 survived when 25 (95% CI, 22-27) were expected to survive. Patients who survive longer may have the opportunity to develop multiple primary melanomas. Patients who encountered all their primary lesions within 2 years may not be subject to this bias. Within the 3 or more melanoma set, 11 patients had all primary melanomas within 2 years. All survived, whereas 9 (95% CI, 8-10) were expected to survive.

CONCLUSIONS: Patients with 3 or more primary melanoma lesions survive longer than anticipated. Such enhanced survival in patients with 3 or more primary melanomas may be consistent with observations of an "immunization effect" in animals inoculated with multiple tumors.


Inverse correlation between p16INK4A expression and NF-kappaB activation in melanoma progression.

Ghiorzo P, Mantelli M, Gargiulo S, Gramigni C, Pastorino L, Banelli B, Villaggio B, Coccia MC, Sementa AR, Garre C, Bianchi-Scarra G.
Hum Pathol. 2004 Aug;35(8):1029-37. Abstract quote  

Expression of p16INK4A, the product of the melanoma susceptibility gene CDKN2A, has been shown to decrease in correlation with tumor progression. P16INK4A is a key regulator of cell-cycle function, and likely interacts with a variety of targets alongside cyclin-dependent kinases (CDKs).

One such target is nuclear factor KB (NF-kappaB), a pleiotropic transcription factor that plays a crucial role in apoptosis, oncogenesis and cell cycle control. NF-kappaB p65 has been shown to be activated in melanoma cell lines but few studies decribe its expression in the tissue. In the present study we focused on synchronous expression of p16INK4A and NF-kappaB p65 and their functional activation in melanoma cell lines and biopsy tissue. Activation of NF-kappaB p65, as observed by electrophoretic mobility shift assay in cell lines, was correlated with expression and cellular localization of the active and inactive forms of its inhibitor, IkappaB-alpha.

In melanocytic lesions, p16INK4A and NF-kappaB p65 expression were inversely correlated with levels of the nuclear component of NF-kappaB p65 increasing from nevi to primary melanomas and metastases.

Expression of polo-like kinase (PLK1) in thin melanomas: a novel marker of metastatic disease.

Kneisel L, Strebhardt K, Bernd A, Wolter M, Binder A, Kaufmann R.

Department of Dermatology Johann Wolfgang Goethe-University, School of Medicine, Frankfurt, Germany Department of Gynaecology, Johann Wolfgang Goethe-University, School of Medicine, Frankfurt, Germany.

J Cutan Pathol 2002 Jul;29(6):354-8 Abstract quote

Background: The maximum thickness of a primary malignant melanoma as measured by Breslow's method is currently the most important prognostic factor. However, some thin melanomas (</= 0.75 mm), which should have an excellent prognosis according to Breslow, can be lethal due to their ability to metastasize.

Methods: In our study, thin malignant melanomas (</= 0.75 mm) from 36 patients were analyzed with immunohistochemical techniques using monoclonal antibodies directed against PLK1 and Ki-67. The immunoreactivity of 22 melanomas which developed metastases within 5 years of follow-up was compared with a group of 14 non-metastasized melanomas. Two independent investigators evaluated stained sections. Differences of PLK1 and Ki-67 indices between melanomas with and without metastases were tested statistically using the Mann-Whitney U-test.

Results: Malignant melanomas with metastases expressed PLK1 at markedly elevated levels compared to melanomas without metastases (median, 60.00% vs. 37.98%; p = 0.000053). The difference of the Ki-67 index between both groups was not significant (median, 6.35% vs. 4.53%; p = 0.150473).

Conclusions: Our results suggest that PLK1 expression in thin melanomas is a reliable marker to identify patients at high risk for metastases.

Poly(adenosine diphosphate-ribose) polymerase 1 expression in malignant melanomas from photoexposed areas of the head and neck region.

Staibano S, Pepe S, Muzio LL, Somma P, Mascolo M, Argenziano G, Scalvenzi M, Salvatore G, Fabbrocini G, Molea G, Bianco AR, Carlomagno C, De Rosa G.

Pathology Section, Department of Biomorphological and Functional Sciences, University Federico II of Naples, 80127 Naples, Italy; Cooperative Melanoma Group, Federico II University, 80127 Naples, Italy.
Hum Pathol. 2005 Jul;36(7):724-31. Abstract quote  

The family of the poly(adenosine diphosphate-ribose) polymerase (PARP) proteins is directly involved in genomic stability, DNA repair, and apoptosis by DNA damage.

In this study, we evaluated the role of PARP-1 in melanoma and its prognostic importance. We studied by immunohistochemistry and Western blot analysis PARP-1 expression in a selected series of 80 primary melanoma of the head and neck region. The results were correlated with tumor thickness and patient's outcome. A follow-up of at least 3 years was available. Fifteen cases of benign melanocytic nevi were used as controls. Normal melanocytes showed only scattered, focal nuclear positivity and were considered as negative for PARP-1 expression by immunohistochemistry (score, 0).

Thirty cases of melanoma (37.5%) showed nuclear expression of PARP-1 in both radial and vertical growth phases. Western blot analysis showed the presence of a high signal for full-length PARP-1 only in the cases with high immunohistochemical (nuclear) expression of protein (score, ++/+++) in both radial and vertical growth phase. A significant correlation was present between PARP-1 expression in vertical growth phase and the thickness of tumor lesion (P = .014); all but one tumor measuring less than 0.75 mm showed no or low PARP-1 expression. No correlation was found between PARP-1 expression in radial growth phase and tumor thickness (P = .38, data not shown).

These data suggest that PARP-1 overexpression is a potential novel molecular marker of aggressive cutaneous malignant melanoma and a direct correlation between PARP-1-mediated inhibition of the apoptosis and biologic behavior of cutaneous malignant melanoma.

Cancer 1991;67:1984-1989

Of patients with a melanoma, another will develop in 1.2-8.2%


Arch Surg 1985;120:115-1159
Ann Surg 1990;212:173-177

Among patients surviving more than 10 years after primary surger, 7-25% develop late recurrences

  Non-familial cases 3% develop second melanomas within 3 years
Familial cases 33% develop second melanomas within 5 years

A follow-up study to investigate the efficacy of initial treatment of lentigo maligna with surgical excision.

Osborne JE, Hutchinson PE.

Department of Dermatology, Leicester Royal Infirmary, Leicester, UK.


Br J Plast Surg 2002 Dec;55(8):611-5 Abstract quote

Recurrence rates following conventional surgery for lentigo maligna (LM) are reported to be between 7% and 15%. However, the studies are few, contain small numbers of patients and have relatively short follow-up.

The principle aim of this study was to determine the efficacy of conventional surgery for LM in a large unbiased sample of all LM presenting in a defined geographical area. All LM cases occurring in Leicestershire between 1987 and 1996 were identified.

Data were gathered from case notes, general practitioners and the Office for National Statistics (for any mortality data) and patients were invited to attend for examination. There were 89 evaluable patients treated with primary excision, representing the largest reported series to date. There was a false positive rate for diagnostic biopsy for LM (when the correct diagnosis was lentigo maligna melanoma, LMM) of 5% (95% confidence interval, CI: 1% to 14%). The initial excision was histologically incomplete in 9% (4% to 17%) of cases. In completely excised lesions (n=81) the observed recurrence rate was 20% (CI: 12% to 30%) at a mean follow-up of 42 months, which is similar to previous reports. However, Kaplan-Meier analysis yielded an estimated probability of recurrence of 31% (CI: 19% to 50%); time to relapse was up to 66 months. The age and sex of the patient and the site of the lesion were not associated with outcome, but, surprisingly, smaller lesions were associated with incomplete excision and recurrence.

Fifteen current lesions were excised with similar success rates: the incomplete re-excision rate was 7% (CI: 0.2% to 32%) and the recurrence rate was 31% (CI: 12% to 83%) at 28 months. The estimated rate of transformation to LMM after initial surgical treatment was 1.5% (CI: 0.3% to 8%), and LMM was not the cause of death in any patient.

These recurrence rates following complete primary excision and re-excision following recurrence were high compared with general expectations, which is largely the result of the method of analysis and the long follow-up. The high rate calls into question the accuracy of the routine histological assessment of clearance. The development of LMM was rare following surgery.

The pathogenesis of local recurrence of melanoma at the primary excision site.

Heenan PJ, Ghaznawie M.

Department of Pathology, Hasanuddin University, Ujungpandang, Indonesia.

Br J Plast Surg 1999 Apr;52(3):209-13 Abstract quote

Local recurrence of melanoma at the primary excision site may imply that the primary excision was incomplete or 'inadequate', and that the recurrence was due to retained primary melanoma cells or occult microsatellites in the adjacent tissue. Pathologists frequently report these tumours in the scar as recurrent or residual melanoma, without further qualification, apparently without considering the possibility that they may be metastases and manifestations of systemic disease.

In this study, 17 of 19 cases of locally recurrent melanoma at the primary excision site showed the histological features of metastasis rather than residual incompletely excised primary melanoma.

Because the prevention of local recurrence is the main reason given in recommendations for wide excision of melanoma beyond complete excision of the primary tumour itself, it is essential that surgeons and pathologists should classify these neoplasms precisely as either persistent incompletely excised primary melanoma or metastatic melanoma.

Outcome of patients with melanoma and histologically negative sentinel lymph nodes.

Gadd MA, Cosimi AB, Yu J, Duncan LM, Yu L, Flotte TJ, Souba WW, Ott MJ, Wong LS, Sober AJ, Mihm MC, Haluska FG, Tanabe KK.

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.

Arch Surg 1999 Apr;134(4):381-7 Abstract quote

HYPOTHESIS: Patients with melanoma and histologically negative sentinel lymph nodes identified by lymphatic mapping have a very good prognosis.

DESIGN: Cohort study with follow-up information obtained from medical records and telephone interviews.

SETTING AND PATIENTS: Of all patients with cutaneous melanoma who underwent intraoperative sentinel lymph node mapping between November 15, 1993, and April 18, 1997, at the Massachusetts General Hospital, Boston, 89 were found to have no evidence of melanoma in their sentinel nodes. Forty-six lesions (51%) were on an extremity and 44 (49%) were of axial location. The median tumor thickness was 1.8 mm (range, 0.36-12.0 mm) and 11 tumors (12%) were ulcerated.

INTERVENTIONS: Patients underwent intraoperative sentinel lymph node mapping with lymphazurin and radiolabeled sulfur colloid. Sentinel lymph nodes were analyzed by standard hematoxylin-eosin staining. Only 2 patients received adjuvant therapy following wide excision of the primary lesion.

MAIN OUTCOME MEASURES: Site of initial recurrence and time to initial recurrence.

RESULTS: The median follow-up for all patients was 23 months (range, 2-54 months). Eleven patients (12%) developed melanoma recurrences, and 78 (88%) patients remain disease free. Regional lymph nodes were the initial site of recurrence in 7 (8%) of 89 patients, and 7 (7%) of 106 mapped basins. Four patients had recurrence without involvement of regional lymph nodes: 2 with distant metastases and 2 with in transit metastases. The median time to recurrence was 12 months (range, 2-35 months). Sentinel lymph nodes were reanalyzed using serial sections and immunoperoxidase stains in 7 patients with recurrence and metastatic melanoma was identified in 3 (43%).

CONCLUSIONS: The risk for melanoma recurrence is relatively low in patients with histologically negative sentinel nodes identified by lymphatic mapping. Longer follow-up will improve our understanding of the prognostic value of this procedure.


Histopathology 1990;17:389-395
Cancer 1978;42:2282-2292
Cancer 1986;57:545-548
Arch Surg 1983;118:41-44
Ann Surg 1988;208:150-161
Virchows Arch 1985;406:179-195

Controversial whether regression is associated with a worse prognosis and risk of metastases

Completely regressed primary cutaneous malignant melanoma with nodal and/or visceral metastases: a report of 5 cases and assessment of the literature and diagnostic criteria.

High WA, Stewart D, Wilbers CR, Cockerell CJ, Hoang MP, Fitzpatrick JE.

Department of Dermatology, The University of Colorado Health Sciences Center, Denver, CO, USA.
J Am Acad Dermatol. 2005 Jul;53(1):89-100. Abstract quote  

BACKGROUND: Partial regression of primary cutaneous malignant melanoma is not uncommon and may predict a higher likelihood of metastasis and decreased survival. Complete histologic regression of a primary cutaneous melanoma is a rarer occurrence, with only 34 cases reported in the English-language or English language-summarized literature.

OBSERVATION: We detail 4 cases of complete histologic regression of primary cutaneous melanoma, discovered at presentation with metastatic disease. A pigmented lesion or its remnant, coupled with historical information, was strongly suggestive of cutaneous melanoma. Histologic examination of the lesions, using multiple levels and immunohistochemical stains, failed to reveal residual melanoma. Our cases are typified by the presence of metastasis of melanoma to regional lymph nodes, with the absence of other suspect skin lesions or malignancies. In addition, we present a fifth case involving a completely regressed lesion on the scalp in a patient with cerebral melanoma metastasis and comment on the implications of this case to accepted diagnostic criteria, proposing that consideration of modification to the criteria be entertained.

CONCLUSION: The concept of completely regressed primary cutaneous melanoma is reviewed and the literature critically appraised. When one considers a diagnosis of completely regressed primary cutaneous melanoma, cases must be well documented and biopsy proven. Patients with metastatic melanoma and an occult primary lesion require a thorough skin examination, with serious consideration given to the possibility of completely regressed cutaneous melanoma.

Partial regression of primary cutaneous melanoma: is there an association with sub-clinical sentinel lymph node metastasis?

Fontaine D, Parkhill W, Greer W, Walsh N.

Department of Pathology, Queen Elizabeth II Health Sciences Centre and Dalhaousie University, Halifax, Nova Scotia, Canada.
Am J Dermatopathol. 2003 Oct;25(5):371-6. Abstract quote  

Whether partial regression of a primary melanoma has an adverse impact on prognosis is controversial. As an indirect mechanism of addressing this question we drew a correlation between the histopathological characteristics of 107 cutaneous melanomas and the presence of sub-clinical metastasis in corresponding sentinel lymph nodes.

Partial regression of the primary tumor, defined as focal replacement of the lesion by a scar, unrelated to a previous biopsy, was observed in 20 (19%) cases in the group as a whole. Excluding cases in which an accurate Breslow thickness of the primary melanoma could not be established and/or the presence of a capsular nevus was detected in the sentinel node, a total of 97 remained. Seventeen cases (Breslow thickness 0.63-9.7; mean 2.4 mm) showed partial regression and 80 (Breslow thickness 0.25-7.00; mean 1.8 mm) were devoid of regression. Of the 17 cases with regression 5 (29%) had nodal metastasis (by histopathology and/or molecular analysis) and of the 80 cases without regression 23 (29%) had nodal metastasis (by one or both evaluations).

Our data reveals no association between partial regression of the primary melanoma and sentinel node involvement by the disease. The Breslow thickness proved to be the only significant independent variable related to nodal metastasis. Of interest, ulceration of the primary lesion was significantly associated with nodal disease on univariate, but not on multivariate, analysis.

While acknowledging that the cohort size may lack the statistical power to demonstrate subtle associations, our data supports the known relevance of tumor thickness and ulceration to regional lymph node metastasis and thereby, to outcome of melanoma in its early stages, but fails to support a similar role for partial regression.


Pathology 1975;7:91-99

This study found regressive change in 12.3% of 437 primary melanomas with less than 10% of patients reporting regression of a pigmented lesion


Arch Dermatol 1987;123:1326-1330

Most ominous study found that patients with thin melanomas with regression in greater than 75% of the lesion, metastases are prone to occur

Lichenoid Tissue Reaction in Malignant Melanoma
A Potential Diagnostic Pitfall

CPT Scott R. Dalton, MC, USA,1,3 Capt Matt A. Baptista, USAF, MC,1,3 COL Lester F. Libow, MC, USA,2 and COL Dirk M. Elston, MC, USA2

Am J Clin Pathol 2002;117:766-770 Abstract quote

Lichenoid tissue reactions can occur in malignant melanoma and may cause partial regression of the lesion. We studied a series of melanomas to determine how frequently lichenoid tissue reaction obscures the diagnosis of malignant melanoma.

We retrospectively reviewed 342 cases of invasive malignant melanoma and melanoma in situ from the head, neck, chest, and back. Of the 342 cases, 23 (6.7%) had a lichenoid tissue reaction obscuring a portion of the lesion. In 6 cases (1.8%), the lichenoid tissue reaction replaced a major portion of the lesion.

Knowledge of this phenomenon can prevent misdiagnosis.

Novel role for RGS1 in melanoma progression.

Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, UCSF Comprehensive Cancer Center, Department of Dermatology, University of California San Francisco, San Francisco, CA 94115, USA.


Am J Surg Pathol. 2008 Aug;32(8):1207-12. Abstract quote

RGS1 (regulator of G protein signaling 1) encodes a member of the regulator of G protein family. Recently, RGS1 was found to be overexpressed in gene expression-profiling studies of melanoma. However, no analyses have been reported of its expression at the protein level in melanoma.

In this study, the potential impact of RGS1 as a molecular prognostic marker for melanoma was assessed using immunohistochemical analysis of a melanoma tissue microarray containing primary cutaneous melanomas from 301 patients. High RGS1 expression was significantly correlated with increased tumor thickness (P=0.0083), mitotic rate (P=0.04), and presence of vascular involvement (P<0.02). Kaplan-Meier analysis demonstrated a significant association between increasing RGS1 expression and reduced relapse-free survival (P=0.0032) as well as disease-specific survival (DSS) (P=0.018) survival. Logistic regression analysis showed RGS1 overexpression to be significantly correlated to sentinel lymph node metastasis (P=0.04). Multivariate Cox regression analysis showed that increasing RGS1 immunostaining had an independent impact on the relapse-free survival (P=0.0069) and DSS (P=0.0077) of this melanoma cohort. In the analysis of DSS, RGS1 expression level was the most powerful factor predicting DSS.

RGS1 immunostaining retained independent prognostic impact even when sentinel lymph node status was included in the prognostic model (P=0.0039). These results validate the role of RGS1 as a novel prognostic marker for melanoma given its impact on the survival associated with melanoma.

A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors.

Goggins WB, Tsao H.

Department of Mathematics, Hong Kong Baptist University, Hong Kong.

Cancer 2003 Feb 1;97(3):639-43 Abstract quote

BACKGROUND: The results of several studies have provided evidence that patients diagnosed with cutaneous melanoma (CM) are at a higher risk of developing a second primary CM than the general population. In this study, the authors examined how the risk of a second primary tumor varied with time from diagnosis of CM and examined the patient-specific factors that modify a CM patient's risk of developing a second primary tumor.

METHODS: Survival curves for time from first CM to second CM were calculated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine which demographic- and disease-related factors influence the risk of a second CM.

RESULTS: Approximately 0.5% of Surveillance, Epidemiology, and End Results (SEER) CM patients were found to have synchronous second primaries. The estimated cumulative probability of having a second primary CM was 0.99% at 1 year after initial CM diagnosis, 2.06% at 5 years, 3.17% at 10 years, and 5.34% at 20 years. Risk was significantly greater for males; older patients; patients with first CM on the face, neck, or trunk; those from the Atlanta, Hawaii, or Connecticut registries; and more recently diagnosed patients. Risk was lower for patients from the Utah registry and those with Stage IV disease.

CONCLUSIONS: The elevated risk for CM among CM survivors appears to be greatest in the first few months, and then subsequently declines. However, the risk for a second CM among CM survivors was found to remain substantially higher than the risk for a first CM in the general population throughout the observation period (> 20 years). Demographic- and disease-related factors substantially modify the risk of a second primary CM.


Cutaneous melanoma. 2nd ed. Philadelphia: JB Lippincott; 1992. p. 200-12.

10YR cure rate 90% <1.5 mm in thickness
<50% survival with 3 mm in thickness
<50% to 75% of patients >4mm in thickness

Stage IV disease 5-17.9% with a median survival of 6 months

  (T1-2, N0) have 10 YRS of 85%
(T3-4, N0) have 10 YRS of 50%
Stage III have 10 YRS of <25%

Small melanomas: a clinical study on 270 consecutive cases of cutaneous melanoma.

Bono A, Bartoli C, Moglia D, Maurichi A, Camerini T, Grassi G, Tragni G, Cascinelli N.

Unit for Cutaneous Oncology, Istituto Nazionale Tumori, Milan, Italy.

Melanoma Res 1999 Dec;9(6):583-6 Abstract quote

The ABCD (asymmetry, border, colour, dimension) criteria represent a commonly used clinical guide for the diagnosis of early cutaneous melanoma (CM). This guide stipulates that CMs usually are more than 6 mm in diameter.

The purpose of this retrospective study was to establish the frequency of occurrence of small (< or =6 mm) melanomas in a clinical context. Our series consisted of 270 consecutive CMs (39 in situ and 231 invasive) in 267 patients. Of these 270 lesions, 47 (17%) were small lesions, ranging from 2 to 6 mm in maximum linear extent, with a median value of 5 mm. Of these small lesions, 14 were in situ and 33 Invasive CMs. The median thickness of the 33 small invasive lesions was 0.31 mm.

The clinical features of CMs were sufficiently distinctive to suggest a diagnosis of CM in half of the cases, irrespective of the invasiveness or not of the lesions. Dermatoscopy was performed on 36 of the small lesions and achieved a correct diagnosis in 72% of the cases. The combination of simple visual examination with dermatoscopy allowed a higher rate of recognition (86%) than when the two methods were considered separately.

Results of our study show that small CMs represent a considerable clinical subset of all CMs. Clinicians must be aware of this fact in their diagnostic activity.


Solitary melanoma confined to the dermal and/or subcutaneous tissue

Evidence for Revisiting the Staging Classification

Glen M. Bowen, MD; Alfred E. Chang, MD; Lori Lowe, MD; Ted Hamilton, MS; Rupa Patel, BA; Timothy M. Johnson, MD


Arch Dermatol 2000;136:1397-1399 Abstract quote

Background  Several patients presented with a single focus of presumed cutaneous metastatic melanoma with an unknown primary tumor based on clinical and histologic staging criteria of the American Joint Committee on Cancer (AJCC). This population is classified as having stage IV disease by the current AJCC staging system, which carries a dismal prognosis (5%-18% 5-year survival). Our clinical observation was that these patients had a higher survival rate than would be expected for stage IV disease. We believe this population represents a subgroup of primary dermal- and or subcutaneously-derived melanoma that simulates cutaneous metastatic melanoma in histologic and clinical presentation but may differ in behavior.

Observations  The database records of 1800 patients from the University of Michigan Melanoma Clinic, Ann Arbor, were retrospectively reviewed to identify the prevalence and survival for patients diagnosed with a single focus of presumed metastatic melanoma to the skin based on accepted histologic and clinical parameters. The prevalence of this population was 0.61% (11 of 1800 patients). The Kaplan-Meier 8-year survival estimate was 83% (95% confidence interval, 58%-100%).

Conclusions  By AJCC convention, these cases are classified as stage IV metastatic disease. Our data suggest that these presumed metastatic tumors do not behave like stage IV metastatic disease to the skin via lymphatic or hematogenous spread from an unknown primary site; rather, they are behaving like primary tumors originating in the dermal and/or subcutaneous tissue.


Prognostic factors in patients with thick cutaneous melanoma (> 4 mm).

Zettersten E, Sagebiel RW, Miller JR 3rd, Tallapureddy S, Leong SP, Kashani-Sabet M.

Melanoma Center, Cutaneous Oncology Program, University of California at San Francisco, Comprehensive Cancer Center, San Francisco, California 94115, USA.

Cancer 2002 Feb 15;94(4):1049-56 Abstract quote

BACKGROUND: The current study was conducted to examine the role of multiple clinical and histologic factors in the prognostic assessment of patients with thick primary melanoma (> 4 mm, classified as T4).

METHODS: A retrospective analysis was performed in 329 patients with T4 cutaneous melanomas who were seen at the University of California at San Francisco Melanoma Center between 1978 and 2000. Fourteen histopathologic features were recorded prospectively by a single dermatopathologist. In addition, 9 clinical factors were analyzed.

RESULTS: Several histologic factors were found to have a significant impact on the survival of patients with T4 melanoma. On univariate analysis, tumor thickness, ulceration, mitotic rate, microsatellites, vascular involvement, and histogenetic type of the primary tumor all were found to have a significant impact on the overall survival rate. Regional lymph node involvement reduced the overall survival of T4 patients dramatically. The 5-year overall survival of patients with lymph node-negative T4 disease was 61%, compared with 30% for those with lymph node-positive disease. When lymph node status was taken into account, tumor thickness, vascular involvement, and ulceration all remained independent predictors of overall survival on multivariate Cox regression analysis. Neither age, gender, nor anatomic location appeared to affect the recurrence-free or overall survival rates.

CONCLUSIONS: Patients with thick primary cutaneous melanomas (> 4 mm) comprise a heterogeneous group. The presence or absence of lymph node involvement, vascular involvement, and ulceration appears to result in significantly divergent overall survival rates in this patient cohort. Consideration of these factors has important implications in the management of patients with T4 melanoma.

Nodular type and older age as the most significant associations of thick melanoma in victoria, australia.

Chamberlain AJ, Fritschi L, Giles GG, Dowling JP, Kelly JW.

Department of Dermatology, Churchill Hospital, Oxford Radcliffe NHS Trust, Old Road, Headington, Oxford OX3 7LJ, England.


Arch Dermatol 2002 May;138(5):609-14 Abstract quote

OBJECTIVES: To explore the clinical associations of thick melanoma and to compare the clinicopathological variables of nodular and superficial spreading types. DESIGN: Cross-sectional study of all invasive primary melanomas recorded by the Victorian Cancer Registry for 1998 and those reviewed by the Victorian Melanoma Service between October 1, 1994, and April 31, 1999.

SETTING: Population-based cancer registry and public hospital-based multidisciplinary melanoma clinic.

PATIENTS: This study included 1422 patients recorded by the Victorian Cancer Registry and 674 patients who had attended the Victorian Melanoma Service; unclassifiable tumor types were excluded, leaving 1144 and 645 patients, respectively, eligible for analysis.

MAIN OUTCOME MEASURES: Melanomas were categorized by thickness into thin (</=1 mm), intermediate (>1-3 mm), and thick (>3 mm) and compared according to patient age, sex, and tumor type and site. Superficial spreading and nodular types were also compared in this manner. Use of the Victorian Melanoma Service database enabled a more comprehensive analysis of historical and phenotypic characteristics.

RESULTS: Thick melanoma was predominantly nodular, occurring in older men, mostly on the head and neck and associated with fewer nevi. Nodular melanoma was thicker and found mostly on the lower limbs or head and neck; it had a greater association with a history of solar keratoses than did superficial spreading melanoma.

CONCLUSION: Nodular type and older age are the most significant associations of thick melanoma.


Clin Lab Med 2000;20:713-729

Controversial term but most have taken it to refer to melanomas less than 1 mm thick although this measurement has ranged from 0.7mm to 1.5mm

If <1mm is used (as recommended by the NIH Consensus Development Conference of 1992), patients have >90% chance of long term survival

Follow-up of patients with a thin melanoma.

Johnson RC, Fenn NJ, Horgan K, Mansel RE.

Department of Surgery, University of Wales College of Medicine, Cardiff, UK.

Br J Surg 1999 May;86(5):619-21 Abstract quote

BACKGROUND: The aim of this study was to determine the value of follow-up in two subgroups of patients with a thin melanoma less than 0.76 mm and 0.76-1.5 mm thick.

METHODS: The study group comprised all patients presenting to the Cardiff Melanoma Clinic from its introduction in 1976 to the end of 1994. All patients attend follow-up according to a strict protocol, determined by the thickness of the original melanoma (less than 0.76 mm, annually; more than 0.76 mm, every 2 months for 2 years, 3 monthly for 2 years, 4 monthly for 1 year and then annually).

RESULTS: In total there were 306 patients with a thin melanoma: 178 with a melanoma thinner than 0.76 mm (group 1) and 128 with a melanoma of 0.76-1.5 mm (group 2). The groups were well matched for age (mean 50.6 (range 8-87) versus 50.6 (range 19-89) years respectively) and length of follow-up (mean 88.6 (range 4-296) versus 80.4 (range 2-296) months). Four patients (2.2 per cent) developed recurrence in group 1 and 16 (12.5 per cent) in group 2. The mean time to recurrence was 84.5 (range 49-143) months in group 1 and 45.3 (range 2-74) months in group 2. All patients in group 1 and 14 of 16 in group 2 died from recurrent disease.

CONCLUSION: Follow-up of patients with a melanoma less than 0.76 mm thick is not worthwhile. All recurrences would have been detected by annual review for 7 years in patients with melanomas between 0.76 and 1.5 mm thick.

High proliferative activity may predict early metastasis of thin melanomas

Sven-Olaf Frahm, MD
Christoph Schubert, MD, PhD
Reza Parwaresch, MD, PhD
Pierre Rudolph, MD, PhD

Hum Pathol 2002;32:1376-1381. Abstract quote

Metastasis of thin melanomas is uncommon and unpredictable.

We prospectively investigated the clinical course of 167 thin melanomas (<1 mm thickness) over a median observation period of 4 years (18 to 87 months). In addition to Breslow thickness, Clark level, and growth phase characteristics, we assessed cellular proliferation by counting mitoses and immunohistochemically using the monoclonal antibody Ki-S5 (Ki-67).

Mitotic and Ki-S5 indices were correlated to tumor thickness, Clarks level, and radial/vertical growth phase (RGP/VGP). However, 5 tumors had proliferation indices above 25% (outside the range of a theoretical normal distribution). Four of these tumors metastasized, and none of the melanomas with lower proliferative activity progressed during the observation period. The metastatic behavior was independent of tumor thickness and Clark level and did not unconditionally coincide with VGP or high mitotic counts.

It is concluded that the immunohistochemical proliferation index may be a powerful predictor of early systemic progression in thin melanomas, which may be helpful in making therapeutic decisions. Further investigations are needed to determine the value of proliferation measurements for the long-term prognosis of thin melanomas.

Histological characteristics of metastasizing thin melanomas: a case-control study of 43 cases.

Guitart J, Lowe L, Piepkorn M, Prieto VG, Rabkin MS, Ronan SG, Shea CR, Tron VA, White W, Barnhill RL.

Department of Dermatology, Northwestern University Medical School, 675 N St Clair, Suite 19-150, Chicago, IL 60611

Arch Dermatol 2002 May;138(5):603-8 Abstract quote

OBJECTIVE: To study clinical and histological features associated with metastasizing thin melanomas (MTMs).

DESIGN: Case-control study of clinicopathological features of patients with MTMs by a panel of 10 dermatopathologists.

SETTING: Members of the North American Melanoma Pathology Study Group selected the cases from the melanoma databases at 8 academic institutions.

PATIENTS: Forty-three patients with MTMs (<1 mm thick) and 42 control subjects without metastasis matched for age, sex, tumor site, and Breslow thickness.


MAIN OUTCOME MEASURES: Clinical (age, sex, site of lesion, stage at diagnosis, metastasis site, disease-free survival, and outcome) and histological (Breslow thickness, Clark level, growth phase, regression, and inflammatory response) features of patients with MTMs vs controls.

RESULTS: There was an overrepresentation of axial tumors among patients with MTMs. Extensive regression was present in 18 patients (42%) with MTM vs 2 matched control subjects (5%) (95% confidence interval, 21%-53%; P =.001). Other histological variables were not significantly different. Two patients had melanomas in situ with subsequent metastasis.

CONCLUSIONS: Thin melanomas with extensive regression represent a group at higher risk for the development of metastasis. Furthermore, the risk of metastasis cannot be dismissed in cases of melanoma in situ.

Expression of Activated TrkA Protein in Melanocytic Tumors
Relationship to Cell Proliferation and Clinical Outcome

Vivi Ann Flørenes, PhD, etal.
Am J Clin Pathol 2004;122:412-420 Abstract quote

We evaluated expression of activated nerve growth factor receptor tyrosine kinase (p-TrkA) by immuno-histochemical analysis in 152 primary and 64 metastatic human melanoma biopsy specimens and 8 nevi.

Membranous, cytoplasmic, and/or nuclear expression of p-TrkA was seen in 54.6% of primary melanomas and 30% of metastases. Membranous p-TrkA was detected in 21.7% of primary and 14% of metastatic melanomas and cytoplasmic immunoreactivity in 28.9% of primary tumors and in 22% of metastases. Significantly fewer metastases than primary tumors expressed nuclear p-TrkA (16% vs 39.5%; P = .006). A significantly higher percentage of nodular than superficial spreading melanomas expressed membranous (40% vs 11%; P < .0001) p-TrkA. Nevi expressed no membranous or cytoplasmic p-TrkA; 63% showed nuclear reactivity. p-TrkA expression varied significantly with thickness of primary tumors (lower expression in thinner lesions: membranous, P = .004; cytoplasmic, P = .001; nuclear, P = .031). An association between ulceration and membranous (P = .054), cytoplasmic (P < .0001), and nuclear (P = .022) p-TrkA expression was found. Membranous p-TrkA significantly predicted decreased overall survival (P = .002). A significant association between membranous p-TrkA and cyclin A (P = .004) and Ki-67 (P < .0001) and between cytoplasmic p-TrkA and cyclin A (P < .0001), Ki-67 (P = .004), and cyclin D3 (P = .027) was found. p-TrkA had no effect on MAPK(ERK1/2) activation. A significant inverse association between cytoplasmic b-catenin and cytoplasmic p-TrkA levels (P = .006) and between nuclear p-TrkA and cytoplasmic E-cadherin (P = .022) was seen.

We present the first evidence of a role for TrkA activation in a subset of melanomas as a predictor of an aggressive phenotype and poor outcome.

Histologic Classification of Tumor-Infiltrating Lymphocytes in Primary Cutaneous Malignant Melanoma A Study of Interobserver Agreement

Klaus J. Busam, MD, Cristina R. Antonescu, MD, Ashfaq A. Marghoob, MD, Kishwer S. Nehal, MD, Dana L. Sachs, MD, Jinru Shia, MD, and Marianne Berwick, PhD

Am J Clin Pathol 2001;115:856-860 Abstract quote

The density and distribution of lymphocytes infiltrating the vertical growth phase of primary cutaneous melanomas has been suggested by several studies to be of prognostic significance. However, few pathologists comment on tumor-infiltrating lymphocytes (TILs), and there is the perception that the assessment of TILs is subject to great interobserver variability.

We studied interobserver agreement on the categorization of TILs; 20 cases of primary cutaneous malignant melanoma with a vertical growth phase component were circulated among 3 pathologists and 3 dermatologists. For each case, TILs were classified as brisk, nonbrisk, or absent according to Clark. Only 1 pathologist (a dermatopathologist) was familiar with the classification of TILs. Observers were given written guidelines and a brief tutorial before their examination of the slides. Our results show that with little instruction, overall agreement among observers was good (kappa values, 0.6 or more), especially among pathologists (kappa values, > 0.7). Three observers had excellent agreement among each other (kappa values, > 0.75).

These findings suggest that the categorization of TILs can be easily taught and can be applied with an acceptable level of reproducibility in routine diagnostic practice.

Prognostic Significance of Extent of Ulceration in Primary Cutaneous Melanoma.

*Melanoma Center, Cutaneous Oncology Program, Cancer Center, University of California daggerDepartment of Surgery, University of California, San Francisco, CA.


Am J Surg Pathol. 2006 Nov;30(11):1396-1400. Abstract quote

Ulceration has been shown to be an adverse prognostic factor in primary cutaneous melanoma. However, the extent of ulceration required for histologic identification and biologic significance is unclear.

We examined the impact of extent of ulceration on melanoma outcome in a cohort of 235 melanoma patients by evaluating the relationship between percentage of ulceration in the vertical growth phase of the primary tumor and 2 outcome parameters: sentinel lymph node status and overall survival. We measured the diameter of the ulcerated area in millimeters over the diameter of the entire vertical growth phase. There was a statistically significant relationship between increasing percentage of tumor ulceration and both sentinel lymph node status as well as overall survival, with a binary cut-off point of 2% for sentinel lymph node status and 5% for overall survival. The percentage of ulceration provides additional prognostic information in predicting sentinel lymph node status and in determining survival in melanoma patients.

These results suggest that no more than minimal ulceration is required to have a prognostic impact on melanoma survival.
Lymphatic vessel density is significantly increased in melanoma.

Giorgadze TA, Zhang PJ, Pasha T, Coogan PS, Acs G, Elder DE, Xu X.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
J Cutan Pathol. 2004 Nov;31(10):672-7. Abstract quote  

Background: Melanoma is well known for its ability to involve regional lymph nodes in the early stage. However, the presence of lymphangiogenesis in melanoma is still controversial due to lack of lymphatic-specific markers. The purpose of this study was to determine the intra- and peritumoral lymphatic vessel density (LVD) using a novel lymphatic vessel-specific marker D2-40 and compare it to general vessel density (GVD) as determined by CD31 immunostaining in a series of melanocytic lesions.

Methods: The intra- and peritumoral GVD and LVD were examined by immunohistochemistry using D2-40 and CD31 antibodies in a series of melanocytic lesions.

Results: We found significantly higher intratumoral LVD in melanomas as compared to either common acquired or dysplastic nevi (p < 0.01). Although peritumoral LVD in melanoma and malignant melanoma in situ was higher compared to nevi, the difference did not reach statistical significance (p = 0.059). There was no significant difference in GVD among the various groups of melanocytic lesions.

Conclusions: Our results show that intratumoral LVD is significantly increased in melanomas compared to benign nevi. The higher intratumoral lymphatic density in invasive melanomas suggests that melanoma cells might promote lymphangiogenesis. In addition, assessment of intratumoral LVD may be potentially useful in the differential diagnosis of melanocytic lesions.

Vascular Involvement in the Prognosis of Primary Cutaneous Melanoma

Mohammed Kashani-Sabet, MD; Richard W. Sagebiel, MD; Carlos M. M. Ferreira, MD; Mehdi Nosrati, BS; James R. Miller III, PhD

Arch Dermatol. 2001;137:1169-1173 Abstract quote

To examine the role of vascular invasion as a prognostic factor in melanoma.

Retrospective survival analysis.

Academic medical center.

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.

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.

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.


Vasculogenic mimicry has no prognostic significance in pT3 and pT4 cutaneous melanoma.

Massi D, Franchi A, Paglierani M, Ketabchi S, Borgognoni L, Reali UM, Santucci M.

Department of Human Pathology and Oncology, University of Florence, Florence, Italy.
Hum Pathol. 2004 Apr;35(4):496-502. Abstract quote  

The concept of vasculogenic mimicry has been introduced to define periodic acid-Schiff (PAS)-positive channels and loops lined by tumor cells, instead of endothelium, able to contribute to microcirculation in uveal melanomas. Previous studies have shown that the PAS-positive patterns are associated with a poor prognosis in uveal melanoma.

The aim of the current study was to investigate whether vasculogenic mimicry has a prognostic impact in pT3 and pT4 cutaneous melanoma. Fifteen patients with pT3 and pT4 cutaneous melanoma who did not experience progression after 10 years of follow-up and 30 matched controls who underwent progression were selected. Tumor sections were stained with PAS reaction, omitting the nuclear counterstaining. For immunohistochemistry, sections were stained with CD31, CD105 (endoglin), and laminin. Differences in the distribution of the PAS-positive patterns and a series of clinicopathological variables were evaluated by the Pearson chi(2) and Mann-Whitney U tests. We observed PAS-positive linear sheets, arcs, elliptical loops, and networks encircling roundish to oval aggregates of melanoma cells. The overall distribution of the PAS-positive patterns did not match with the blood microvessels' architecture as detected by immunohistochemical analysis. No statistically significant differences in the distribution of PAS-positive patterns were found between cases and controls. The presence of a parallel pattern correlated significantly with thickness (P = 0.04), whereas an inverse correlation was found with vessel area (P = 0.05).

In conclusion, our results suggest that there is a mismatch between vasculogenic mimicry and tumor angiogenesis and do not support any prognostic role of vasculogenic mimicry in thick cutaneous melanoma.

Each scheduled visit should include:
Complete history and physical examination
Complete blood count
Liver function tests
Serum lactic dehydrogenase level

If one or more tests are abnormal, additional sophisticated testing should be performed

Stage I
Stage II
Every 6 months for 2 years, then annually thereafter
Stage III
Every 3 months for 1 year, every 4 months for the second year, and every 6 months for years 3-5
All patients
Annual visits from year 6 onward

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008

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