Reduced p16 and increased cyclin D1 and pRb expression are correlated with progression in cutaneous melanocytic tumors.

The immunohistochemical expression of cell cycle proteins p16, cyclin D1, and pRb was assessed in 112 benign and malignant melanocytic tumors and correlated with tumor progression, prognosis, and outcome. Comparing benign and malignant tumors, there were significant differences in the median score for all 3 proteins, with decreased p16 (P = .000001), increased cyclin D1 (P = .01), and increased pRb in melanomas (P = .01). There was a progressive loss of expression of p16 with progression from benign naevi to primary melanomas and to metastases. p16 was significantly decreased in primary tumors from melanoma patients who developed recurrent disease (P = .0000013). Cyclin D1 and pRb showed a progressive increase in expression from benign to malignant tumors but with relative decreases in the more advanced tumors (thick primaries and metastatic melanomas). Alterations in cell cycle proteins involved in G1/S transition are implicated in melanocytic tumor progression and have a potential role in diagnosis and prognostication.

So-called "malignant blue nevus": a clinicopathologic study of 23 patients.

BACKGROUND: Melanomas that arise in association with or that resemble blue nevi are extremely rare and have been termed "malignant blue nevi." The authors report on a single-institutional clinicopathologic study of "blue nevus-like melanomas" (BNLMs). METHODS: Twenty-six patients were identified with a "malignant blue nevus" over 29 years at the Sydney Melanoma Unit. Twenty-three patients were included in the current study after pathologic review. Clinical outcomes of those patients were compared with the outcomes in a matched control group of patients with melanoma (matched for age, sex, Breslow thickness, Clark level, ulceration, and anatomic site). RESULTS: The median patient age was 44 years, and men comprised 65% of the patients. The tumors were distributed evenly among skin sites, and their median Breslow thickness was 5.5 mm. After a median follow-up of 36.5 months, there was no difference in survival (P = .702) between patients with BNLM and patients in the control group. CONCLUSIONS: BNLMs tended to present at a more advanced stage, with thicker primary tumors, but had a metastatic pattern comparable to and was not more aggressive in behavior than other types of melanoma. The authors concluded that BNLMs should be treated in the same way as any other melanoma variants based on clinical staging and pathologic prognostic indices.

The complex relationships between sentinel node positivity, patient age, and primary tumor desmoplasia: analysis of 2303 melanoma patients treated at a single center.

BACKGROUND: Recent studies have shown that younger age is associated with a greater likelihood of positive sentinel node (SN) status in patients with localized melanoma. This is a paradoxical situation because it is well known that younger patients have a far more favorable overall survival rate than older patients. In addition, desmoplastic melanomas are associated with a lower frequency of SN positivity, although this is less well documented. METHODS: The outcome for 2303 cutaneous melanoma patients undergoing sentinel lymph node biopsy (SLNB) at the Sydney Melanoma Unit between 1993 and 2006 was examined to clarify the role of patient age and desmoplastic histogenetic type on SN positivity. RESULTS: By univariate analysis, patients aged <40 years had a higher SN positivity rate (22.6%) than patients aged > or =40 years (15.4%; P < .004). Features associated with SN positivity were tumor thickness, mitotic rate, ulcerative state, and nondesmoplastic histogenetic type (all P < .001). Patient sex and primary melanoma site were not statistically significantly associated. Multivariate analyses revealed that only tumor thickness, patient age, nondesmoplastic type (all P < .001), and ulceration (P < .026) were independently associated with SN positivity. Key prognostic determinants such as total number of disease-positive nodes (both SNs and non-SNs) and site of first relapse did not vary according to age. CONCLUSIONS: Tumor thickness, patient age, desmoplastic histogenetic type, and primary melanoma ulceration were all independently associated with SN status. The factors underlying the paradox of a poorer survival rate in older patients despite a lower incidence of positive SNs remain unclear.

A sentinel node biopsy does not increase the incidence of in-transit metastasis in patients with primary cutaneous melanoma.

BACKGROUND: It has been suggested that performing a sentinel node biopsy (SNB) in patients with cutaneous melanoma increases the incidence of in-transit metastasis (ITM). METHODS: ITM rates for 2018 patients with primary melanomas > or =1.0 mm thick treated at a single institution between 1991 and 2000 according to 3 protocols were compared: wide local excision (WLE) only (n = 1035), WLE plus SNB (n = 754), and WLE plus elective lymph node dissection (n = 229). RESULTS: The incidence of ITM for the three protocols was 4.9%, 3.6%, and 5.7%, respectively (not significant), and as a first site of recurrent disease the incidence was 2.5%, 2.4%, and 4.4%, respectively (not significant). The subset of patients who were node positive after SNB and after elective lymph node dissection also had similar ITM rates (10.8% and 7.1%, respectively; P = .11). On multivariate analysis, primary tumor thickness and patient age predicted ITM as a first recurrence, but type of treatment did not. Patients who underwent WLE only and who had a subsequent therapeutic lymph node dissection (n = 149) had an ITM rate of 24.2%, compared with 10.8% in patients with a tumor-positive sentinel node treated with immediate dissection (n = 102; P = .03). CONCLUSIONS: Performing an SNB in patients with melanoma treated by WLE does not increase the incidence of ITM.

The prognostic importance of tumor mitotic rate confirmed in 1317 patients with primary cutaneous melanoma and long follow-up.

BACKGROUND: The late Dr. Vincent McGovern (1915 to 1983) was an international authority on melanoma pathology and one of the first to suggest that assessment of tumor mitotic rate (TMR) might provide useful prognostic information. Data for a large cohort of patients, now with extended follow-up, whose tumors had been assessed by Dr. McGovern were analyzed to reassess the independent prognostic value of TMR in primary localized, cutaneous melanoma. METHODS: Information was extracted from the Sydney Melanoma Unit database for 1317 patients treated between 1957 and 1982 for whom there was complete clinical information and whose primary lesion pathology, which included tumor thickness, ulcerative state, and TMR, had been assessed by Dr. McGovern. All these assessments were made according to the recommendations of the Eighth International Pigment Cell Conference, held in Sydney in 1972 under the auspices of the International Union Against Cancer. Factors predicting melanoma-specific survival were analyzed with the Cox proportional hazards regression model. RESULTS: Stage, according to the recently revised American Joint Committee on Cancer Staging System (which is based on tumor thickness and ulceration) was the most predictive factor for survival (P<.0001). This was followed by primary lesion site (P<.0001), patient age (P=.0005), and TMR (P=.008). CONCLUSIONS: TMR was confirmed to be an important independent predictor of survival of patients with primary cutaneous melanoma. However, its predictive value was less than it was when assessed according to the 1982 revisions of the 1972 TMR recommendations.

Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas.

BACKGROUND: The prognosis for patients with localized primary cutaneous melanoma is known to depend principally on tumor thickness, and to a lesser extent on ulcerative state and Clark level. We have recently found in an analysis of 3661 patients that tumor mitotic rate (TMR) is also an important prognostic parameter, ranking second only to tumor thickness. However, few studies have assessed the accuracy and reproducibility with which these features of a melanoma are recorded by histopathologists. AIM: To assess interobserver reproducibility of major pathologic prognostic parameters in cutaneous melanoma. METHODS: Single hematoxylin and eosin-stained slides of 69 dermally invasive primary cutaneous melanomas were circulated among six pathologists with differing experience in the assessment of melanocytic tumors. The observers independently determined the tumor thickness, Clark level of invasion, ulcerative state, and TMR for each lesion. Intraclass correlation coefficients and kappa scores for multiple ratings per subject were calculated. RESULTS: The intraclass correlation coefficients were 0.96 for tumor thickness and 0.76 for TMR. The kappa scores were 0.83 for ulcerative state and 0.60 for Clark level. These results indicated excellent agreement among the pathologists for measurements of tumor thickness, ulcerative state, and TMR and fair to good agreement for Clark level. CONCLUSIONS: Appropriately trained and experienced histopathologists can assess prognostically important features of melanomas accurately and reproducibly. Given our recent finding of the significance of TMR in determining prognosis, it is important that this feature be assessed by a standardized method and documented for all primary cutaneous melanomas.

Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center.

BACKGROUND: The current study was performed to determine whether tumor mitotic rate (TMR) is a useful, independent prognostic factor in patients with localized cutaneous melanoma. METHODS: From the Sydney Melanoma Unit database, 3661 patients with complete clinical information and details of primary tumor thickness, ulcerative state, and TMR were studied. TMR was expressed as mitoses per mm(2) in the dermal part of the tumor in which most mitoses were seen, as recommended in the 1982 revision of the 1972 Sydney classification of malignant melanoma. To determine which was the more prognostically useful method of grouping TMR, two separate methods (A and B) were used. Factors predicting melanoma-specific survival were analyzed using the Cox proportional hazards regression model. RESULTS: Patients with a TMR of 0 mitoses/mm(2) had a significantly better survival than those with 1 mitosis/mm(2) (P < 0.0001) but no significant survival differences were recorded for the stepwise increases from 1-2, 2-3, 3-4, and 4-5/mm(2). Tumor thickness, ulceration, and TMR were closely correlated, whether TMR was grouped using Method A (0, 1-4, 5-10, and >/= 11 mitoses/mm(2)) or Method B (0-1, 2-4, and >/= 5 mitoses/mm(2)). However, Cox regression analysis indicated that the TMR was a highly significant independent prognostic factor, particularly when grouped according to Method A, in which it was second only to tumor thickness as the most powerful predictor of survival (P < 0.0001). CONCLUSIONS: TMR is an important independent predictor of survival for melanoma patients. If confirmed by studies from other centers, it has the potential to further improve the accuracy of melanoma staging, as well as to define more rigidly the risk categories for patients entering clinical trials.