Number of primary melanomas is an independent predictor of survival in patients with metastatic melanoma

BACKGROUND:

A history of multiple primary melanomas (PMs) has been associated with improved survival in patients with early stage melanoma, but whether it also is correlated with survival in patients with metastatic melanoma is unknown. The authors sought to address the latter question in the current study.

METHODS:

Patients with metastatic melanoma diagnosed at the Melanoma Institute Australia between 1983 and 2008 were identified. Overall survival (OS) was calculated from date of first distant metastasis. Survival analysis was performed using the Kaplan‐Meier method, log‐rank tests, and multivariate Cox proportional hazards models.

RESULTS:

Of 2942 patients with metastatic melanoma, 2634 (89.5%) had 1 PM and 308 (10.5%) had >1 PM. Factors that were associated independently with shorter OS were site of metastasis, including the brain (hazard ratio [HR], 2.41; 95% confidence interval [CI], 2.07‐2.81; P < .001) and nonlung viscera (HR, 1.92; 95% CI, 1.67‐2.22; P < .001, vs lymph node/subcutaneous/soft tissue), age >60 years (HR, 1.23; 95% CI, 1.12‐1.36; P < .001), shorter disease‐free interval from PM to first distant metastasis (≤12 months vs >36 months: HR, 1.62; 95% CI, 1.39‐1.89; P < .001), and fewer PMs (1 vs >1; HR, 1.26; 95% CI, 1.08‐1.47; P = .004).

CONCLUSIONS:

A history of multiple PM was an independent predictor of improved survival for patients with metastatic melanoma. The results indicate that a history of multiple PMs should be incorporated into multivariate analyses of prognostic factors and treatment outcomes. Cancer 2012. © 2012 American Cancer Society.     

Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients

Background:

The urokinase plasminogen activator (uPA) system is one of the best-investigated protease systems, both under physiological and pathological conditions, including various types of cancer. However, effects of co-expression of members of the uPA system in soft-tissue sarcoma (STS) patients at the protein level in both tumour tissue and serum have not been investigated yet.

Methods:

We examined 82 STS patients for protein levels of uPA, PAI-1and uPAR in tumour tissue and serum by ELISA.

Results:

A significant correlation between high antigen levels of uPA, PAI-1 or uPAR in tumour tissue, and of uPAR in serum, with poor outcome of STS patients was found for the first time. Most strikingly, we observed an additive effect of combined uPA, PAI-1 or uPAR levels in tumour tissue extracts with uPAR levels in serum on patients'' prognosis. High uPA/uPAR, PAI-1/uPAR and uPAR/uPAR antigen levels in tumour tissue/serum were associated with a 5.9-fold, 5.8-fold and 6.2-fold increased risk of tumour-related death (P=0.003, 0.001 and 0.002, respectively) compared with those patients who displayed low levels of the respective marker combination.

Conclusion:

As expression of members of the uPA system in tumour tissue and serum is additively correlated with prognosis of STS patients, our results suggest that combinations of these biomarkers can identify STS patients with a higher risk of tumour-related death.     

TYRP1 mRNA expression in melanoma metastases correlates with clinical outcome

Background:

Clinical outcome of patients with high-risk melanoma cannot be reliably predicted on the basis of classical histopathological examination. Our study aimed to determine in melanoma metastases a gene expression profile associated with patient survival, and to identify and validate marker(s) of poor clinical outcome.

Methods:

Skin and lymph node metastases from melanoma patients (training population) were used to identify candidate prognostic marker(s) based on DNA microarray analysis. Additional skin metastases (validation population) were used to assess the prognostic value of the first ranked gene by real-time PCR.

Results:

We performed microarray analysis in the training population and generated a list of 278 probe sets associated with a shorter survival. We used the first ranked gene, tyrosinase-related protein 1 (TYRP1), further measured its expression in the validation population by real-time PCR and found it to be significantly correlated with distant metastasis-free survival (DMFS), overall survival (OS) and Breslow thickness. We also found that it was fairly well conserved in the course of the disease regardless of the delay to metastasis occurrence. Finally, although Tyrp1 protein (immunohistochemistry (IHC)) was only detected in about half of the samples, we showed that its expression also correlated with Breslow thickness.

Conclusion:

Our data indicate that TYRP1 mRNA expression level, at least in skin metastases, is a prognostic marker for melanoma, and is particularly useful when prognostic pathology parameters at the primary lesion are lacking. Its conserved expression further supports its use as a target for therapy.     

p27 expression correlates with short-term, but not with long-term prognosis in breast cancer

New prognostic and predictive factors are needed to adjust more appropriate therapy for individual patients after operation. p27 is a cell cycle regulator, and a low tissue expression of this protein has been shown to correlate with poor prognosis in colorectal, lung, gastric, prostate, and breast cancer. In this study on 197 breast cancer patients with a median follow-up of 17 years, the prognostic value of immunohistochemical p27 expression was evaluated. After 5 years of follow-up patients with a p27 expression in less than 50% of the tumor cells had a significantly lower survival rate than those with an expression above this level (p=0.01). However, after longer follow-up the difference decreased and was no longer significant at 7 years (p=0.1) or when the entire follow-up period was examined (p=0.67). Tests for associations showed that a low p27 expression correlated with a high histologic grade, a high S-phase fraction (SPF), an advanced TNM stage and negative hormone receptor status. In conclusion: Tissue expression of p27 is a significant predictor of 5-year, but not of 10- or 15-year breast cancer specific survival.     

Ultrathin primary is a marker for worse prognosis in lymph node–positive cutaneous melanoma

BACKGROUND:

Lymph lymph node metastasis from melanoma ≤0.50 mm (ultrathin) is an infrequent event. However, because many newly diagnosed melanomas are ultrathin, a significant proportion of patients who present with lymph node disease have an ultrathin melanoma. The authors hypothesized that ultrathin melanomas that present with lymph node metastasis represent biologically aggressive lesions with a worse prognosis.

METHODS:

The Surveillance, Epidemiology, and End Results registry data were queried to identify patients with cutaneous melanoma who presented with lymph node metastasis diagnosed between 1998 and 2008. Hazard ratios (HRs) from Cox proportional hazards regression models were used to compare disease‐specific survival (DSS) between various tumor depths.

RESULTS:

In total, 6134 patients with lymph node‐positive melanoma were identified and stratified according to tumor depth, including 588 (10%) with a tumor depth ≤0.50 mm, 519 (8%) with a tumor depth from 0.51 to 1.00 mm, 1669 (27%) with a tumor depth from 1.01 to 2.00 mm, 1871 (31%) with a tumor depth from 2.01 to 4.00 mm, and 1487 (24%) with a tumor depth >4.00 mm; and the respective 5‐year DSS rates were 63%, 76%, 75%, 60%, and 43%. Multivariable analysis confirmed a similar trend in HRs for DSS: The HR was 1.00 for a tumor depth ≤0.50 mm (reference category) and 0.64 (P < .001), 0.65 (P < .001), 0.95 (P = .57), and 1.42 (P < .001) for tumor depths of 0.51 to 1.00 mm, 1.01 to 2.00 mm, 2.01 to 4.00 mm, and >4.00 mm, respectively. This association of tumor depth with DSS persisted for N1 and N2 disease but not for N3 disease.

CONCLUSIONS:

Ultrathin melanoma (≤0.50 mm) was identified as a marker of poor prognosis in the setting of lymph node metastasis. These results may improve recommendations for adjuvant therapy, surveillance protocols, and risk stratification for clinical trials. Cancer 2013. © 2013 American Cancer Society.     

CD44v3 levels in primary cutaneous melanoma are predictive of prognosis: assessment by the use of tissue microarray

Despite the use of sentinel node biopsy techniques, the search continues for other strategies to improve the accuracy of estimating prognosis in melanoma patients. Various biomarkers have previously been studied for use in this role, but none has yet achieved acceptance in routine practice. We have applied the novel technology of tissue microarray for the high throughput screening of a cohort of 120 primary cutaneous melanoma specimens for expression of the transmembrane glycoprotein CD44, splice variant 3 (v3), which has previously been implicated in tumor progression. A highly significant correlation between CD44v3 expression and Breslow thickness, Clark's level and patient age was demonstrated (Spearman correlation p < 0.001). Regarding clinical outcome, CD44v3 expression was shown to be significantly associated with better outcome (chi(2) = 7.2219, p = 0.0072). Furthermore, subgroup analysis revealed a sequentially improved survival probability associated with the intensity of CD44v3 staining (chi(2) = 12.5162, p = 0.0058). Analysis in a Cox multivariate model, however, did not show CD44v3 to be independently predictive of prognosis. The implications of these findings are considered, and the use of CD44v3 as a potential prognostic marker or a target for therapeutic manipulation are discussed.     

皮肤恶性黑色素瘤患者预后的影响因素分析

目的分析皮肤恶性黑色素瘤(MM)患者预后的影响因素。方法选取74例接受手术联合免疫治疗的皮肤MM患者,采用Cox比例风险回归模型分析影响皮肤MM患者预后的危险因素。结果 74例皮肤MM患者中,死亡33例。单因素分析结果显示,不同TNM分期、肿瘤破溃情况、淋巴结转移情况、Clark分级皮肤MM患者的2年生存率比较,差异均有统计学意义(P<0.05);不同病理类型皮肤MM患者的2年生存率比较,差异无统计学意义(P>0.05)。Cox比例风险回归模型分析结果显示,TNM分期为Ⅲ～Ⅳ期、有淋巴结转移、有肿瘤破溃、Clark分级为Ⅲ～Ⅴ级是影响手术联合免疫治疗后皮肤MM患者预后的独立危险因素(P<0.01)。结论手术联合免疫治疗对皮肤MM具有较好的效果,临床上应重视患者的TNM分期、淋巴结转移情况、肿瘤破溃情况和Clark分级对皮肤MM患者预后的影响。     

High LIFr expression stimulates melanoma cell migration and is associated with unfavorable prognosis in melanoma

Increased or decreased expression of LIF receptor (LIFr) has been reported in several human cancers, including skin cancer, but its role in melanoma is unknown. In this study, we investigated the expression pattern of LIFr in melanoma and assessed its prognostic value. Using tissue microarrays consisting of 441 melanomas and 96 nevi, we found that no normal nevi showed high LIFr expression. LIFr staining was significantly increased in primary melanoma compared to dysplastic nevi (P = 0.0003) and further increased in metastatic melanoma (P = 0.0000). Kaplan–Meier survival curve and univariate Cox regression analyses showed that increased expression of LIFr was correlated with poorer 5-year patient survival (overall survival, P = 0.0000; disease-specific survival, P = 0.0000). Multivariate Cox regression analyses indicated that increased LIFr expression was an independent prognostic marker for primary melanoma (P = 0.036). LIFr knockdown inhibited melanoma cell migration in wound healing assays and reduced stress fiber formation. LIFr knockdown correlated with STAT3 suppression, but not YAP, suggesting that LIFr activation might stimulate melanoma cell migration through the STAT3 pathway. Our data indicate that strong LIFr expression identifies potentially highly malignant melanocytic lesions at an early stage and LIFr may be a potential target for the development of early intervention therapeutics.     

小儿肝母细胞瘤的临床病理特点及预后

目的 探讨小儿肝母细胞瘤的临床病理特点及预后。方法 对２４例小儿肝细胞瘤进行临床病理分析和组织学分型,其中１８例作７种标记的免疫组化研究。对手术病例进行随访观察。结果 上皮型肝母细胞瘤２２例,其中胎儿型１３例,胚胎型７例和间变型３例,上皮间叶混合型２例。细胞角蛋白、甲胎蛋白、Ｓ－１００蛋白和波型蛋白在肿瘤细胞浆的表达分别为１４例、１０例、９例和４例,癌胚抗原、Ｐ５３和Ｐ１６蛋白在肿瘤细胞核的表达分     

Tissue-Type plasminogen activator (tPA) in breast cancer: relationship with clinicopathological parameters and prognostic significance

Summary Background. Tissue-type plasminogen activator (tPA) is a serine protease primarily involved in the intravascular dissolution of blood clots. High intratumoral tPA levels are associated with prognosis in several human tumors. In addition, tPA has been shown to be an estrogen-inducible protein in human breast cancer cell lines. The aim of the present study was to analyze the cytosolic tPA content in primary breast carcinomas and its potential clinical value. Materials and methods. tPA was measured by a solid-phase enzyme immunoassay in tumor cytosol samples obtained from 800 patients with breast cancer. The median follow-up period was of 49.2 months. Results. Cytosolic tPA levels ranged widely in breast carcinomas (median: 3.9; range: 0.1– 315.3 ng/mg protein). tPA levels were significantly lower in large tumors, as well as in those showing poor differentiation, estrogen (ER) or PgR-negativity, aneuploidy, or a high S-phase fraction. In addition, low tPA intratumoral levels were associated with a high probability of both shortened relapse-free and overall survival in all patients and in the subgroup with node-negative tumors. However, our results did not show any significant relationship between intratumoral tPA levels and prognosis in the different subgroups of patients, stratified according to the type of systemic adjuvant therapy received (chemotherapy, tamoxifen or chemotherapy plus sequential tamoxifen). Conclusion. The results of the present investigation indicate that low intratumoral tPA levels are associated with aggressiveness and poor prognosis in breast cancer patients. However, the study suggests that tPA levels do not predict response to systemic adjuvant therapy.     

Prognostic factors in cutaneous desmoplastic melanoma

BACKGROUND:

Desmoplastic melanoma (DM) is a rare subtype of melanoma that is characterized by malignant spindle cells separated by prominent, fibrocollagenous stroma. Primary melanomas either may be entirely desmoplastic or almost entirely desmoplastic (pure DM [pDM]) or may exhibit a desmoplastic component admixed with a nondesmoplastic component (combined DM [cDM]).

METHODS:

Patients who were diagnosed between 1993 and 2007 at a single institution with clinically localized, primary cutaneous melanoma (PCM) that contained a desmoplastic component and who underwent sentinel lymph node (SLN) biopsy were identified. Clinical and pathologic features of the primary tumors were correlated with DM type, SLN status, and patient outcome.

RESULTS:

Two hundred fifty‐two patients (167 men, 85 women) were identified (median age, 61 years). The median tumor thickness was 2.0 mm. One hundred twenty‐three patients (48.8%) had pDM, and 129 patients (51.2%) had cDM. Overall, 17 patients (6.7%) had positive SLN status, including 12 patients with cDM and 5 patients with pDM. Because of the low SLN‐positive rate, a statistically significant difference in SLN status between patients with cDM (8.5%) and patients with pDM (4.9%; P = .25) could not be demonstrated. Older patient age, being a man, positive SLN status, and increasing tumor thickness were associated significantly with poorer disease‐free survival (P < .05), although only the latter 2 variables were independently predictive. In addition, cDM type (P = .017) was associated significantly and independently with a shorter time to recurrence.

CONCLUSIONS:

In this largest study to date of patients with DM who underwent SLN biopsy, the SLN‐positive rate in patients with DM was lower than that in patients with conventional melanoma. The results indicated that DM type is associated significantly and independently with the time to recurrence and should be evaluated routinely in all patients with PCM. Cancer 2010. © 2010 American Cancer Society.     

CDCA5在皮肤恶性黑色素瘤中的表达及其与预后相关性的生物信息学分析

目的:探讨CDCA5在皮肤恶性黑色素瘤(cutaneous malignant melanoma,CMM)中的表达、相关信号通路及其与患者预后之间的关系.方法:应用Oncomine和GEPIA数据库研究CDCA5基因在不同肿瘤组织中的表达情况以及与患者预后关系.此外,还收集了我院41例黑色素瘤患者及41例正常皮肤病例进...     

食管原发性恶性黑色素瘤的临床病理观察

目的：探讨食管原发性恶性黑色素瘤的诊断、鉴别诊断及生物学行为。方法：报道l例食管原发性恶性黑色素瘤，对其进行光镜观察、免疫组织化学及特殊染色检测，并复习文献。结果：食管原发性恶性黑色素瘤多见于中老年人，常发生于食管中、下段1／3处，大体呈息肉状；光镜下瘤细胞异型性明显，呈梭形、圆形或不规则型，以梭形细胞为主。肿瘤细胞胞核体积大，核仁清晰、染色质丰富，部分细胞胞浆内有棕黄色颗粒；免疫组化结果肿瘤细胞显示波形蛋白（Vimentin）、S-100蛋白、HMB45和Melanoma—pan阳性；不表达神经特异性烯醇化酶（neuron—speciiticenolase，NSE）、白细胞共同抗原（1eukocytecommonantigen，LCA）、细胞角蛋白（cytokeratin，CK）、嗜铬素蛋白-A（chromograninA，Cgh）、人绒毛膜促性腺激素（humanchorionicgonadotropin，HCG）、上皮膜抗原（epithelial membtane antigen，EMA）、高分子量CK、CK18、小细胞肺癌（smallcell lungcancer，SCLC）和突触素（synaptophysin）等。结论：食管原发性恶性黑色素瘤是一种罕见肿瘤，由于其症状与食管其它肿瘤相似，在活检或手术前很难确诊，对发生于中老年人的食管中、下段息肉样肿物应考虑原发性恶性黑色素瘤的可能。     

Survival of patients with visceral metastatic melanoma from an occult primary lesion: A retrospective matched cohort study

Background: Malignant melanoma presents as metastatic disease without an apparent primary in about 4% of cases. These are referred to as occult primary melanoma (OPM). It is not known whether these represent de novo malignant transformation in non-cutaneous sites or the disappearance of an unrecognised primary, perhaps on an immunological basis. We hypothesised that OPM might have a superior prognosis compared to patients with similar disease extent from a known primary lesion (KPM).Patients and methods: We performed a retrospective cohort survival study of 146 patients with OPM and visceral metastases treated at the Sydney Melanoma Unit between 1983 and 1996. A control group of patients with KPM was matched for age, sex and site of visceral metastases. Survival was measured from the date of diagnosis of visceral metastases.Results: Patients with OPM had a median survival of 233 days, significantly longer than the 176 days for those with KPM (P = 0.024; logrank test). Multivariate analysis allowing for simultaneous or prior involvement of lymph nodes, subcutaneous tissues or bone, and site of visceral involvement showed a significantly superior survival for OPM (hazard ratio (HR): 0.72; 95% confidence interval (CI): 0.55–0.93). A small part of the effect was explained by treatment, but models allowing for this still showed a significantly longer survival.Conclusions: Survival was longer in OPM patients. This may reflect an intrinsically superior host-tumour interaction.     

EphA2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma

EphA2 is a member of the Eph family of receptor tyrosine kinases, which interact with cell-bound ligands known as ephrins. EphA2 expression was investigated by immunohistochemistry with an anti-EphA2 monoclonal antibody in 80 patients with esophageal squamous cell carcinoma (ESCC) who had undergone surgery. EphA2 overexpression was positive in 40 of the 80 patients (50%). A significant correlation was observed between EphA2 expression and regional lymph node metastasis (p=0.023), number of lymph node metastases (p=0.011) and poor degree of tumor differentiation (p=0.004). The survival rates of EphA2-positive patients were poorer than those of EphA2-negative patients (p=0.014). The 5-year survival rate of patients without EphA2 overexpression was 68%, whereas that of patients with EphA2 overexpression was 29%. EphA2 expression was also investigated in 7 ESCC cell lines (TE-1, -2, -8, -13, -15, TT and TTn) and 1 immortalized human esophageal keratinocyte cell line (CHEK-1). Western blotting revealed different levels of EphA2 expression in the 8 cell lines. EphA2 was expressed at a high level in the ESCC cell lines compared to CHEK-1. EphA2 phosphorylation was demonstrated in all cell lines. Northern blot analysis showed that EphA2 mRNA expression in TE-1 was greater than that in the other ESCC cell lines. The observation of small gaps on Western blot analysis of the ESCC cell lines suggests that there may be a mechanism for EphA2 regulation at the point of translation. In conclusion, EphA2 overexpression appears to be related to poor degree of tumor differentiation and lymph node metastasis in ESCC. Consequently, patients with EphA2 overexpression have a poorer prognosis than those without. EphA2 is a potential target to prevent ESCC cells spreading into the lymphatic drainage.     

High nevus counts confer a favorable prognosis in melanoma patients

A high number of nevi is the most significant phenotypic risk factor for melanoma and is in part genetically determined. The number of nevi decreases from middle age onward but this senescence can be delayed in patients with melanoma. We investigated the effects of nevus number count on sentinel node status and melanoma survival in a large cohort of melanoma cases. Out of 2,184 melanoma cases, 684 (31.3%) had a high nevus count (>50). High nevus counts were associated with favorable prognostic factors such as lower Breslow thickness, less ulceration and lower mitotic rate, despite adjustment for age. Nevus count was not predictive of sentinel node status. The crude 5‐ and 10‐year melanoma‐specific survival rate was higher in melanomas cases with a high nevus count compared to those with a low nevus count (91.2 vs. 86.4% and 87.2 vs. 79%, respectively). The difference in survival remained significant after adjusting for all known melanoma prognostic factors (hazard ratio [HR] = 0.43, confidence interval [CI] = 0.21–0.89). The favorable prognostic value of a high nevus count was also seen within the positive sentinel node subgroup of patients (HR = 0.22, CI = 0.08–0.60). High nevus count is associated with a better melanoma survival, even in the subgroup of patients with positive sentinel lymph node. This suggests a different biological behavior of melanoma tumors in patients with an excess of nevi.