The history and future of melanoma staging

The evolution and progressive refinement of an internationally accepted melanoma staging system over the last 50 years has resulted in much greater accuracy and increased utility, but the staging process has become more complex and less intuitive. This raises the question of whether melanoma staging should continue to develop with ever-increasing levels of complexity, or whether attempts should be made to produce an alternative system that is simpler and more intuitive. The current, TNM-based American Joint Committee on Cancer (AJCC) staging system for melanoma incorporates only some of the prognostic factors of proven significance. However, the information that is now available about these and other, well-documented prognostic factors allows accurate prediction of an individual melanoma patient's prognosis using a computer-generated estimate. Thus an alternative staging strategy that could be considered in the future would be to use such an estimate to obtain a numerical score for each patient, based on all available information agreed to be of prognostic relevance. A stage grouping could then be assigned on the basis of that score, according to previously determined score ranges for each stage and substage. The advantages of such a system would be that it would allow more reliable comparison of treatment results within and between institutions, and would provide more equivalent stratification groups for patients entering clinical trials of new therapies and those entering adjuvant therapy trials. A further advantage would be that because there would be a direct link between staging and prognostic estimate, such a system would be more readily able to be understood in an intuitive fashion.     

Expression and prognostic significance of iNOS in uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Disease metastasis occurs in half of the patients and is uniformly fatal despite systemic therapy. Inducible nitric oxide synthase (iNOS) is associated with disease progression in various malignancies including cutaneous melanoma. In this retrospective cohort, we examined the prognostic value of iNOS in UM by performing immunohistochemistry on paraffin‐embedded sections of primary tumors (90 patients) and matched primary and metastatic hepatic tumors (19 patients) with complete histopathological and clinical data. We show that iNOS is expressed in UM (57% of the patients) and high iNOS levels significantly (p = 0.04; hazard ratio (HR) = 2.3) predict disease‐specific survival (DSS) as assessed by Kaplan‐Meier analysis and univariate Cox's proportional hazards regression model. Furthermore, high iNOS expression in the UM primary tissue was significantly associated with metastatic disease and vice versa. Expression of iNOS in hepatic metastases significantly (p = 0.02) predicted a shortened survival as assessed by Kaplan‐Meier analysis. However, iNOS did not appear to be a significant (p = 0.16; HR = 1.9) factor in the multivariate Cox's regression analysis performed together with the clinical parameters tumor diameter, tumor cell type, and tumor location in which only tumor diameter predicted DSS. In conclusion, iNOS predicts DSS in UM and may play a role in disease progression but it is not an independent prognostic factor.     

Osteopontin as a molecular prognostic marker for melanoma

BACKGROUND: Osteopontin has been suggested as a marker of disease progression in patients with melanoma because of its overexpression in recent microarray analyses. However, its prognostic role in melanoma has not been fully defined. METHODS: Osteopontin expression status was examined using immunohistochemical analysis of a tissue microarray that contained primary cutaneous melanomas from 345 patients. The correlation between osteopontin expression and several histologic markers for melanoma was assessed by using the Chi-square test and the Le directional test. The impact of osteopontin expression on recurrence-free survival (RFS) and disease-specific survival (DSS) of patients with melanoma was examined using Cox regression and Kaplan-Meier analyses. The impact of increasing osteopontin expression on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis. RESULTS: High osteopontin expression was associated with increased tumor thickness (P = .037), Clark level (P = .035), and mitotic index (P = .046). Kaplan-Meier analysis demonstrated an association between osteopontin expression and reduced RFS (P < .03) and DSS (P = .05). Multivariate Cox regression analysis demonstrated that high osteopontin immunostaining had an independent impact on the DSS of this melanoma cohort (P = .049). In addition, osteopontin expression was significantly predictive of SLN metastasis (P = .009) and SLN burden, as assessed by the mean number of SLN metastases (P = .0025). Multivariate logistic regression analysis demonstrated an independent role for osteopontin expression in predicting SLN status (P = .0062). CONCLUSIONS: The current results validated the role of osteopontin as an independent prognostic marker for melanoma and provided new evidence for its predictive role in melanoma lymph node metastasis.     

Update on the melanoma staging system: the importance of sentinel node staging and primary tumor mitotic rate

The 7(th) Edition of the AJCC Staging Manual includes a detailed summary of melanoma staging and prognosis. The revisions are summarized in this article, along with details on two key aspects of melanoma staging: the incorporation of mitotic rate of the primary melanoma and the key role of the sentinel lymph node biopsy (SLNB) in determining accurate staging for clinically occult nodal metastases. Primary tumor mitotic rate was introduced as a major criterion for melanoma staging and prognosis that replaces the Clark's level of invasion, and is now proven to be an important independent adverse predictor of survival. Analysis of the AJCC melanoma staging database demonstrated a significant inverse correlation between primary tumor mitotic rate (histologically defined as mitoses/mm(2) ) and survival. The use of SLNB reliably identifies melanoma patients with nodal micrometastases, enabling clinicians to identify patients with occult nodal metastases that would otherwise take months or years to become clinically palpable The number of nodal metastases was the most significant independent predictor of survival among all patients with stage III disease, including among patients with nodal micrometastases, and continues to be a primary criterion for defining Stage III melanoma. A clinical scoring system model and multivariate predictive tool under the auspices of the AJCC has led to a first-generation web-based predictive tool (www.melanomaprognosis.org).     

Sentinel node metastasis mitotic rate (SN‐MMR) as a prognostic indicator of rapidly progressing disease in patients with sentinel node‐positive melanomas

Risk stratification of sentinel lymph node biopsy (SNB)‐positive patients with malignant melanoma differs among current classification systems. To improve classification of patients with rapidly progressive disease who may profit from adjuvant therapy with novel immune or targeted treatment modalities, a single‐center retrospective analysis was performed including all melanoma patients diagnosed with a positive SN at a university‐based skin cancer center over a 10‐year period (2002–2012) (96 of 419 patients). Sentinel node metastasis mitotic rate (SN‐MMR) and further histologic parameters were determined by blinded histological re‐evaluation and correlated with clinical follow‐up (overall [OS], melanoma‐specific [MSS], and disease‐free survival [DFS]). Median follow‐up was 53 months. In univariate analyses, SN tumor penetrative depth (TPD), maximum tumor diameter (MTD), number of positive SN, SN‐MMR and the S‐, Rotterdam, RDC, Hannover I and II classification systems correlated with OS, MSS and DFS. Multivariate Cox regression analyses showed that a binary classification system based only on the SN‐MMR (<1 vs. ≥1 mitoses/mm²) was the strongest independent prognostic indicator for all endpoints analyzed. Kaplan‐Meier analyses confirmed binary SN‐MMR to be superior to stratify patients into high‐ and low‐risk groups (45.45% vs. 87.92% 5‐yr MSS). The general prognostic validity of the published SN classification systems was confirmed. The novel SN‐MMR classification system may improve discrimination of patients with slowly and rapidly progressive disease. We therefore propose its implementation into clinical practice as the SN‐MMR can be easily and reliably determined in routine pathology reports. Its prognostic value for the selection of patients amenable to adjuvant therapies should be studied in clinical trials.     

Implementation of the 7th edition AJCC staging system: Effects on staging and survival for pT1 melanoma. A Dutch population based study

In the 7^th edition of the AJCC staging system, the mitotic rate criterion replaced Clark level to increase correct classification of high‐risk thin melanoma patients (pT1B). Additionally, sentinel node biopsy (SNB) was recommended for nodal staging of pT1B melanomas. The aim of this article was to evaluate the effects on pT1 substaging and clinical implications in the national pT1 melanoma population. All pT1 melanomas diagnosed in the Netherlands between 2003 and 2014 were selected from the Netherlands Cancer Registry (IKNL). Patients were stratified by cohort according to AJCC edition: (1) 2003–2009 (6^th) and (2) 2010–2014 (7^th). Relative survival was calculated to estimate melanoma‐specific survival. A total of 29.546 pT1 melanoma patients were included. The pT1b proportion increased from 10.1% in Cohort 1 to 21.5% in Cohort 2. The proportion of performed SNBs per cohort increased: for pT1b melanomas alone from 4.5% to 13.0%. SNB positivity rate decreased from 10.5% to 8.8% for the entire pT1 population, and for pT1b melanomas from 11.3% to 8.6%. At 5 years, the relative survival rate was similar for pT1a and pT1b in both cohorts, namely, pT1a 100% vs pT1b 97% (Cohort 1), and pT1a 100% vs pT1b 98% (Cohort 2). The 7^th edition of the AJCC staging system has caused an increased number of patients to undergo SNB, without an increase in SNB positivity rate. Survival between pT1 subgroups remains similar. The mitotic rate criterion for pT1b classification and the recommendation to perform SNB for pT1b melanomas should be reconsidered.     

Primary malignant melanoma of the lip

Melanoma of the lip is a very rare clinical entity. As such, no large studies are available to help in diagnosis and treatment. We report our results on 11 patients with lip melanoma. Patients with lip melanoma should be approached in a similar fashion to patients with other cutaneous melanomas.     

The prognostic value of the mitotic activity index in patients with primary breast cancer who were not treated with adjuvant systemic therapy

Background. At the St Gallen meeting of 2001 it was agreed to select high-risk patients for adjuvant systemic therapy by lymph node status, tumor size, age, hormone receptor status, and histological grade. In The Netherlands it was chosen to use either the histological grade or the mitotic activity index (MAI). The aim of this study was to retrospectively evaluate the independent prognostic value of the MAI in primary breast cancer patients, who were not treated with adjuvant systemic therapy, on relapse-free survival (RFS) and overall survival (OS). Patients and methods. The data of 137 systemically untreated patients with primary breast cancer diagnosed between 1992 and 1996, of whom MAI was assessed, were retrospectively collected. The MAI was correlated to classical prognostic factors and we determined the prognostic value of the MAI, the histological grade and other prognostic factors. Results. The median observation time was 4.2 years. The MAI showed a positive correlation to lymph node status (P <; 0.001) and a negative correlation to age (P = 0.005), menopausal status (P <; 0.001) and the ER and PgR status (r _s = –0.390 [ER], r _s = –0.440 [PgR], both P < 0.001). A high MAI ( 15) predicted a reduced RFS and OS in the Kaplan–Meier analysis (P = 0.0070 and P = 0.0017, respectively). Also in the multivariate analysis, the MAI showed to be an independent predictor of poor RFS (P = 0.035), in addition to lymph node status. However, the MAI did not predict for OS, in contrast to tumor size and lymph node status. Conclusion. The present study confirms that the MAI is an independent prognostic factor for RFS, but not for OS and may be useful for daily clinical practice.     

Gamma Knife radiosurgery for intracranial metastatic melanoma: an analysis of survival and prognostic factors

Objective of this study was to evaluate retrospectively the effectiveness of Gamma Knife radiosurgery for intracranial metastatic melanoma and to identify prognostic factors related to survival. Twenty-six patients with intracranial metastases (72 lesions) from melanoma underwent Gamma Knife radiosurgery. In 14 patients (54%) whole-brain radiotherapy (WBRT) was performed as part of the initial treatment, and in 12 patients (38%) immunotherapy and/or chemotherapy was given after Gamma Knife radiosurgery. The median tumor volume for Gamma Knife radiosurgery treated lesions was 1.72 cm³. The median prescribed radiation dose was 18 Gy (range 8–22 Gy) typically prescribed to the isodose at the tumor margin. Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival. Overall median survival was 6 months after Gamma Knife radiosurgery, and 1-year survival was 25%. The median survival from the onset of brain metastases was 9 months and from the original diagnosis of melanoma was 50 months (range 4–160 months). There were no major acute or late GKS complications. In univariate testing, the Karnofsky score equal to or higher than 90% (P < 0.01, log-rank test), supratentorial localization (P < 0.001, log-rank test), intracranial tumor volume less than 1 cm³ (P < 0.02, log-rank test), and absence of neurological signs or symptoms before Gamma Knife radiosurgery (P < 0.003, log-rank test) were significant favorable factors for survival. In multivariate regression analyses, the most important predictors associated with increased survival were a KPS 90 (P < 0.023), female sex (P < 0.004), supratentorial localization (P < 0.01), and absence of neurological symptoms (P < 0.008). Radiosurgery is a noninvasive, safe, and effective treatment option for patients with single or multiple intracranial metastases from melanoma. Female sex, Karnofsky score 90, supratentorial localization and lack of symptoms before the Gamma Knife radiosurgery were good independent predictors of survival.     

Expression of the mitotic checkpoint gene MAD2L2 has prognostic significance in colon cancer

Aneuploidy and genetic instability are a hallmark of colorectal cancer and other solid tumors, and they are thought to enhance tumor progression. The gene MAD2L2 (mitotic arrest deficient 2-like 2) encodes the spindle checkpoint protein MAD2L2 (or MAD2B), a key component of a surveillance system that delays anaphase until all chromosomes are correctly oriented. Defects in this mitotic checkpoint are known to contribute to genetic instability, i.e., numerical and structural aberrations of chromosomes. We have previously identified MAD2L2 as significantly upregulated in locally restricted colorectal tumors by gene expression profiling. So far, MAD2L2 has not been reported to play a major role in human cancer in contrast to its homologue MAD2. To address this question, 118 histologically confirmed colorectal lesions were analyzed by quantitative real-time PCR for expression of MAD2L2, and compared to normal colon tissue from 11 patients. Twenty-five out of 118 tumor samples (21%) showed MAD2L2 overexpression of 3-fold or more compared to normal colon, and the fraction of overexpressing tumors increased with tumor stage. Correspondingly, protein levels of MAD2L2 were found to be significantly upregulated in tumors as compared to matched normal tissue. Tumors with upregulated MAD2L2 expression had significantly higher numbers of aberrant mitotic figures (anaphase bridges), an indication of chromosomal instability. Elevated expression of MAD2L2 was significantly correlated with reduced patient survival. By multivariate analysis, MAD2L2 expression was retained as an independent prognostic parameter for patient survival. Thus, our results demonstrate that overexpression of MAD2L2 correlates with bad prognosis in colorectal cancer.     

The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma

BACKGROUND: In addition to Breslow depth, the authors previously described how increasing mitotic rate and decreasing age predicted sentinel lymph node (SLN) metastases in patients with melanoma. The objectives of the current study were to verify those previous results and to create a prediction model for the better selection of which patients with melanoma should undergo SLN biopsy. METHODS: The authors reviewed 1130 consecutive patients with melanoma in a prospective database who underwent successful SLN biopsy. After eliminating patients aged <16 years and patients who had melanomas that measured <1 mm, 910 remaining patients were reviewed for clinical and pathologic features and positive SLN status. Univariate association of patient and tumor characteristics with positive SLN status was explored by using standard logistic regression techniques, and the best multivariate model that predicted lymph node metastases was constructed by using a backward stepwise-elimination technique. RESULTS: The characteristics that were associated significantly with lymph node metastasis were angiolymphatic invasion, the absence of regression, increasing mitotic rate, satellitosis, ulceration, increasing Breslow depth, decreasing age, and location (trunk or lower extremity compared with upper extremity or head/neck). Previously reported interactions between mitotic rate and age and between Breslow depth and age were confirmed. The best multivariate model included patient age (linear), angiolymphatic invasion, the number of mitoses (linear), the interaction between patient age and the number of mitoses, Breslow depth (linear), the interaction between patient age and Breslow depth, and primary tumor location. CONCLUSIONS: Younger age, increasing mitotic rate (especially in younger patients), increasing Breslow depth (especially in older patients), angiolymphatic invasion, and trunk or lower extremity location of the primary tumor were associated with a greater likelihood of positive SLN status. The current results support the use of factors beyond Breslow depth to determine the risk of positive SLN status in patients with cutaneous melanoma.