Interobserver variability of histopathological prognostic parameters in cutaneous malignant melanoma: impact on patient management.

Clinical management of primary cutaneous melanomas is based on histopathological staging of the tumour. The aim of this study was to investigate, in a non-selected population in clinical practice, the agreement rate between general pathologists and pathologists experienced in melanoma in terms of the evaluation of histopathological prognostic parameters in cutaneous malignant melanomas, and to what extent the putative variability affected clinical management. A total of 234 cases of invasive cutaneous malignant melanoma were included in the study from the Stockholm-Gotland Healthcare Region in Sweden. Overall interobserver variability between a general pathologist and an expert review was 68.8-84.8%. Approximately 15.5% of melanomas ≤1 mm were re-classified either as melanoma in situ or melanomas >1 mm after review. In conclusion, review by a pathologist experienced in melanoma resulted in a change in recommendations about surgical excision margins and/or sentinel node biopsy in subgroups of T1 melanomas.

2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: a randomised, multicentre trial.

BACKGROUND: Optimum surgical resection margins for patients with clinical stage IIA-C cutaneous melanoma thicker than 2 mm are controversial. The aim of the study was to test whether survival was different for a wide local excision margin of 2 cm compared with a 4-cm excision margin. METHODS: We undertook a randomised controlled trial in nine European centres. Patients with cutaneous melanoma thicker than 2 mm, at clinical stage IIA-C, were allocated to have either a 2-cm or a 4-cm surgical resection margin. Patients were randomised in a 1:1 allocation to one of the two groups and stratified by geographic region. Randomisation was done by sealed envelope or by computer generated lists with permuted blocks. Our primary endpoint was overall survival. The trial was not masked at any stage. Analyses were by intention to treat. Adverse events were not systematically recorded. The study is registered with ClinicalTrials.gov, number NCT01183936. FINDINGS: 936 patients were enrolled from Jan 22, 1992, to May 19, 2004; 465 were randomly allocated to treatment with a 2-cm resection margin, and 471 to receive treatment with a 4-cm resection margin. One patient in each group was lost to follow-up but included in the analysis. After a median follow-up of 6·7 years (IQR 4·3-9·5) 181 patients in the 2-cm margin group and 177 in the 4-cm group had died (hazard ratio 1·05, 95% CI 0·85-1·29; p=0.64). 5-year overall survival was 65% (95% CI 60-70) [corrected] in the 2-cm group and 65% (40-70) in the 4-cm group (p=0·69). INTERPRETATION: Our findings suggest that a 2-cm resection margin is sufficient and safe for patients with cutaneous melanoma thicker than 2 mm. FUNDING: Swedish Cancer Society and Stockholm Cancer Society.

Bilateral prophylactic mastectomy in Swedish women at high risk of breast cancer: a national survey.

BACKGROUND/OBJECTIVE: This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences. METHODS: Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period. RESULTS: A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low (3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1unanticipated secondary operation. CONCLUSIONS: Bilateral prophylactic mastectomy is safe and efficacious in reducing future breast cancer in asymptomatic women at high risk. Unanticipated reoperations are common. Given the small number of patients centralization seems justified.

Vascular endothelial growth factor receptor 2 and downstream p38 mitogen-activated protein kinase are possible candidate markers of intrinsic resistance to adjuvant endocrine treatment in steroid receptor positive breast cancer.

A cross talk between tyrosine kinase receptors and mitogen-activated protein kinases (MAPKs) is proposed as involved in endocrine resistance. We wanted to investigate intratumoral levels of vascular endothelial growth factor receptor 2 (VEGFR2) and p38 MAPK in relation to relapse-free (RFS) and breast cancer corrected survival (BCCS) after adjuvant endocrine treatment, mainly tamoxifen for 2 or 5 years. We also wanted to investigate these markers in relation to early and late recurrences. VEGFR2 (n = 381) and p38 (n = 174) were determined by enzyme-linked immuno-sorbent assays in tumor homogenates from primary BC diagnosed 1993-1996. Wide ranges of VEGFR2 and p38 proteins were found; median 0.72 pg/µg DNA (range 0.0-11.66), and 0.04 pg/µg DNA (range 0.0-6.79), respectively. Detectable levels of p38 were registered in 65% and classified positive. Higher VEGFR2 were correlated to higher VEGF (P = 0.005), p38 MAPK (P = 0.018), negative ER (P = 0.008), larger tumors (P = 0.001), histopathological grade III (P = 0.018), distant metastasis (P = 0.044), shorter RFS (P = 0.013), and shorter BCCS (P = 0.017). Expression of p38 was significantly correlated with negative PgR (P = 0.044) and with early relapses (P = 0.021), while no difference was seen during the later follow-up period (P = 0.73). Higher VEGFR2 had a significant negative impact on both early (P = 0.029) and later recurrences (P = 0.018), while VEGF only predicted later relapses (P = 0.037). Our preliminary results suggest higher intratumoral levels of VEGFR2 and p38 MAPK as candidate markers of intrinsic resistance for adjuvant endocrine therapy.

Age-specific trends of survival in metastatic breast cancer: 26 years longitudinal data from a population-based cancer registry in Stockholm, Sweden.

Treatment of metastatic breast cancer (MBC) has evolved during the last decades but it is largely unknown whether this has led to improved survival in the general MBC population. Based on the regional, population-based breast cancer registry, we identified 5,463 patients diagnosed with MBC in Stockholm County during 1979-2004. Patients were divided into five cohorts based on the year of first MBC diagnosis and observed and relative survival were compared across the cohorts after adjustment for potential confounders. A significant trend of better survival over time was demonstrated for patients 60 years or younger (P < 0.001, by log-rank test for trend), but not for older patients (P = 0.12) or for the whole MBC population (P = 0.13). The adjusted observed survival of patients ≤ 60 years was significantly improved in the 2000-2004 cohort (P < 0.001, hazard ratio = 0.7, 95% confidence interval = 0.58-0.84), corresponding to a clinically significant increase of median survival with more than 3 months and absolute increase of 5-year survival with 8% or more compared to previous periods. Similarly, relative survival analysis indicated a 31% decreased mortality for the younger subpopulation in the 2000-2004 cohort (P < 0.001). Systemic adjuvant treatment was a negative prognostic factor after distant recurrence. Treatment advancements in MBC are not reflected by better survival for the whole MBC population. An improvement is only observed after the year 2000 and is restricted to younger patients.

Activated ERK1/2 and phosphorylated oestrogen receptor alpha are associated with improved breast cancer survival in women treated with tamoxifen.

The aim of this study was to investigate the expression of activated (phosphorylated) ERK1/2, oestrogen receptor alpha phosphorylated at S118 (ERalphaS118), and HER2 in primary breast cancer, and to make correlations with the outcome of tamoxifen therapy. We performed immunohistochemical analysis to determine the expression of HER2, ERalphaS118, and activated ERK1/2 in tumours obtained from 279 women with primary breast cancer. HER2 status was also estimated by fluorescence in situ hybridisation. We identified 108 women with ERalpha-positive tumours who had received adjuvant tamoxifen. Activated ERK1/2 (pERK1/2) and ERalphaS118 were found to be associated with each other and with other factors correlated with good prognosis. HER2 was inversely associated with pERK1/2. Positive staining for pERK1/2 (particularly intense staining) indicated better relapse-free survival (P=0.05) and a trend towards better breast cancer-corrected survival in women treated with tamoxifen. To conclude, this study shows that activated ERK1/2 and ERalphaS118 are associated with improved survival. The poorer outcome in HER2-positive women who receive adjuvant tamoxifen cannot be explained by the crosstalk between HER2 and ERalphaS118 via activated ERK1/2 alone.

When does my treatment start?--The continuum of care for patients with head and neck cancer.

BACKGROUND AND PURPOSE: The clinical workup of patients with head and neck (H&N) cancer is often time-consuming. The overall time involved is obviously important to the treatment results, since delays in time can increase the risk for clinical upstaging resulting in a worse outcome. Although for ethical considerations, time delay is impossible to study in randomised trials. Major reorganisations for this group of patients have taken place in Stockholm during the 1990s. In this study, we measured the duration of the overall continuum of care experienced by the patients, in different time periods during the 1990s. MATERIALS AND METHODS: Two hundred and two patients from the population base of southern Stockholm were identified during different time periods. The continuum of care was identified as the period between the first presentation of the patient to the health care system to the first date of the patient's treatment for his/her cancer. This period was divided into several intervals reflecting the patient's perspective of his or her continuum of care. These intervals were then compared. RESULTS: Median time from first consultation to start of treatment increased between 1994 and 1999 from 67 to 89 days (P = 0.018). The increase of time occurred from referral from first care provider to ENT-specialist, from first visit to ENT-specialist to date of diagnosis. CONCLUSIONS: Different parameters such as duration of the continuum of care must be monitored before and after reorganisations.

Incidence of fractures causing hospitalisation in prostate cancer patients: results from the population-based PCBaSe Sweden.

BACKGROUND: Prostate cancer patients have an increased risk of fractures as a consequence of skeletal metastases and osteoporosis induced by endocrine treatment. Data on incidence of fractures and risks in subgroups of men with prostate cancer are sparse. Our aim with this study is to report the risk of fractures among men with prostate cancer in a nationwide population-based study. PATIENTS AND METHODS: We identified 76,600 Swedish men diagnosed with prostate cancer 1997-2006 in the Prostate Cancer Data Base (PCBaSe) Sweden and compared the occurrence of fractures requiring hospitalisation with the Swedish male population. RESULTS: Only men treated with gonadotropin releasing-hormone (GnRH) agonists or orchiectomy had increased incidence and increased relative risk of fractures requiring hospitalisation. Men treated with GnRH agonists had 9.8 and 6.3/1000 person-years higher incidence of any fracture and hip fracture requiring hospitalisation than the general population. The corresponding increases in incidence for men treated with orchiectomy were 16 and 12/1000 person-years, respectively. Men treated with orchiectomy, GnRH agonists, and antiandrogen monotherapy, had SIR for hip fracture of 2.0 (95% Confidence Interval 1.8-2.2), 1.6 (95% CI 1.5-1.8) and 0.9 (95% CI 0.7-1.1), respectively. Men treated with a curative intent (radical prostatectomy or radiotherapy) or managed with surveillance had no increased risk of fractures. Older men had the highest incidence of fractures while younger men had the highest relative risk. CONCLUSION: Prostate cancer patients treated with GnRH agonists or orchiectomy have significantly increased risk of fractures requiring hospitalisation while patients treated with antiandrogen monotherapy had no increase in such fractures. In absolute terms the excess risk in men treated with GnRH agonists corresponded to almost 10 extra fractures leading to hospitalisation per 1000 patient-years. Effects on bone density should be considered for men on long-term endocrine treatment. Unwarranted use of orchiectomy and GnRH agonists should be avoided.

Metastatic potential in renal cell carcinomas ≤7 cm: Swedish Kidney Cancer Quality Register data.

BACKGROUND: Renal cell carcinoma (RCC) represents 2-3% of all malignancies and accounts for approximately 90% of all kidney malignancies. An increasing proportion of RCCs are discovered incidentally, and the average tumor diameter at diagnosis has decreased over the last few decades. Small RCCs have often been regarded by many as relatively harmless. OBJECTIVE: The objective was to evaluate the incidence of local T-category distribution and lymph node and distant metastases in relation to tumor size in RCCs ≤7 cm in a nationally based patient population. DESIGN, SETTING, AND PARTICIPANTS: Data were extracted from the National Swedish Kidney Cancer Register containing 3489 RCCs diagnosed between 2005 and 2008. This is a population-based registry including 99% of all RCCs diagnosed nationwide. The study included 2033 patients having a tumor ≤7 cm in diameter. MEASUREMENTS: The size of the tumors was compared with sex, age, cause of diagnosis, Fuhrman grade, RCC type, and TNM category. RESULTS AND LIMITATIONS: Most RCCs were discovered incidentally and incidence correlated inversely to tumor size. There were 887 (43%) patients with category T1a tumors, 836 (40%) with category T1b, 174 (8%) with T3a, 131 (6%) with T3b/c, and 12 (1%) patients had invasion of adjacent organs (T4). A total of 309 (15%) patients had lymph node and/or distant metastases. Of the 177 1- to 2-cm RCCs, category T3 tumors were identified in three patients and lymph node and/or distant metastases were identified in 8 (5%). Only for tumors ≤1 cm was there neither advanced stage nor metastasis. The occurrence of locally advanced growth, lymph node and distant metastases, and high tumor grade correlated to tumor size. Patients with Fuhrman grade III or IV had a four-fold greater risk of metastases than grades I or II. CONCLUSIONS: Lymph node and distant metastases occur even in small RCCs. Risk of metastases increases with tumor size. The data clearly show that small RCCs also have a malignant potential and should be properly evaluated and adequately treated.

Prognosis of patients with breast cancer: causes of death and effects of time since diagnosis, age, and tumor characteristics.

PURPOSE: The proportion of women living with a diagnosis of breast cancer in developed countries is increasing. Because breast cancer-specific deaths decrease with time since diagnosis, it is important to assess the burden of other causes of death in women diagnosed with breast cancer. METHODS: Different causes of death within 10 years from diagnosis were assessed in 12,850 women younger than 75 years of age with stage 1 to 3 breast cancer diagnosed in Stockholm and Gotland regions 1990 to 2006. Flexible parametric survival models were used to estimate hazard ratios over time since diagnosis by tumor characteristics and age at diagnosis. RESULTS: The proportion of deaths attributed to breast cancer ranged from 95.0% among women younger than age 45 years at diagnosis to 44.5% among women age 65 to 74 years. The proportions of circulatory system-specific deaths and deaths resulting from other causes increased with older age at diagnosis. Patients with one to three positive lymph nodes were more likely to die as a result of breast cancer during the first 10 years of follow-up compared with women without positive lymph nodes. Women with estrogen receptor (ER) -positive tumors had the same risk of dying as a result of breast cancer 5 years after diagnosis compared with women with ER-negative tumors. CONCLUSION: Lymph node negativity is an important long-term predictor of more favorable prognosis. The nature of the relationship between ER status and risk of dying as a result of breast cancer after 5 years of follow-up requires further investigation. Circulatory system diseases are an important cause of death, especially in women diagnosed with breast cancer at an older age.

ProMIS™ can serve as a da Vinci® simulator--a construct validity study.

PURPOSE: The purpose of this study was to investigate if the ProMIS™ simulator could serve as a training platform for the da Vinci® surgical system and if this constellation could prove construct validity. MATERIALS AND METHODS: The da Vinci system was connected to the ProMIS simulator, which registered objective data concerning how the surgeon performed in the box environment related to time, path, and smoothness. Five experienced robotic surgeons passed four different surgical tasks with progressive difficulty. A novice group-constituted of 13 consultants and 6 residents, none of them with any previous experience in the da Vinci system-passed the same tasks and the data were compared with the results from the expert group. RESULTS: A statistically significant difference between experts and novices was demonstrated in all tasks concerning time and smoothness. For the parameter path, significant difference was only noted in the more complex tasks. CONCLUSIONS: Our study showed that ProMis could differentiate between experienced robotic surgeons and novices, thereby proving construct validity. Smoothness appeared to be the most sensitive objective parameter in our study. Tasks with high complexity are recommended when designing the program for robotic training.

Esophageal stricture after radiotherapy in patients with head and neck cancer: experience of a single institution over 2 treatment periods.

BACKGROUND: Risk factors for development of a stricture of the upper esophagus after radiotherapy for head and neck cancer are poorly defined. METHODS: This was a retrospective case-control study of patients diagnosed and treated for esophageal stricture after radiotherapy for head and neck cancer. RESULTS: The incidence of esophageal stricture after external beam radiation therapy (EBRT) was 3.3%. Seventy patients with stricture and 66 patients without stricture were identified. A multivariate analysis showed that there was increased risk of stricture in receiving enteral feeding during EBRT or in receiving a mean dose of >45 Gy to the upper esophagus. CONCLUSIONS: Enteral feeding during EBRT is strongly associated with the development of stricture of the esophagus, as is a mean dose of >45 Gy to the upper esophagus. Treatment of the stricture with Savary-Gilliard bougienage or through scope balloon dilatation is safe and successful but often has to be repeated.

Paget's disease of the nipple in a population based cohort.

BACKGROUND: Paget's disease of the nipple is a rare form of breast cancer characterised by the presence of intraepidermal tumour cells. It is often associated with ductal carcinoma in situ (DCIS) and/or invasive cancer in the breast parenchyma. We have studied the presentation and symptoms of Paget's disease, local control and breast cancer corrected survival following breast conserving surgery or mastectomy. PATIENTS AND METHODS: The study is based on 223 women with histological verified Paget's disease of the nipple diagnosed between 1976 and 2001 at 13 Swedish hospitals. All women s charts were reviewed. All recurrences and deaths were registered. A comparison was made for differences in breast cancer-corrected survival (BCS) and disease-free survival (DFS) in univariate analyses. RESULTS: The median follow-up was 12 (4-28) years. In a vast majority (98%), the main presenting symptom was eczema or ulceration of the nipple. The diagnosis of an underlying breast malignancy was established in 79% of the women before surgery. A cone excision of the nipple-areola complex was performed in 43 women and 169 women had a mastectomy. Eleven elderly women were not operated. One hundred and seventeen women had a non-invasive Paget of which 40 had an underlying DCIS. Invasive cancer was seen in 68 women. In 38 cases the histopathological report did not state if the tumour was invasive or not. Thirty-three women died from breast cancer. In operated women BCS and DFS at 10 years were 87% and 82%, respectively. The 10-year BCS for non-operated patients (n = 11) was 34%. At 10 years, the cumulative local recurrence rate was 9%, 8% among women undergoing mastectomy and 16% among those treated with breast conserving surgery. In univariate analysis the type of surgery, cone excision or mastectomy, had no statistically significant impact on BCS or DFS. Risk factors for breast cancer death and recurrence were having an underlying invasive cancer compared with an in situ carcinoma and having a palpable tumour in the breast. CONCLUSION: The main presenting symptoms were eczema or ulceration of the nipple. Patients with non invasive Pagets disease of the nipple had an excellent cancer outcome. Selected patients with Paget's disease of the nipple were treated with breast conserving surgery with survival rates similar to those achieved with mastectomy.