Frequency, localization, and types of gastrointestinal stromal tumor-associated neoplasia.

BACKGROUND: In recent years, increasing evidence of second neoplasms associated with gastrointestinal stromal tumors (GIST) has been found. Numerous case reports, mostly retrospective studies and a few reviews, have been published. To our knowledge, however, no systematic review or meta-analysis of the existing data has been performed so far. AIM: To prepare a compilation, as complete as possible, of all reported second tumor entities that have been described in association with GIST and to systematically analyze the published studies with regard to frequency, localization, and types of GIST-associated neoplasms. METHODS: The MEDLINE and EBSCO databases were searched for a combination of the keywords GIST/secondary, synchronous, coincident/tumor, neoplasm, and relevant publications were selected by two independent authors. RESULTS: Initially, 3042 publications were found. After deletion of duplicates, 1631 remained, and 130 papers were selected; 22 of these were original studies with a minimum of 20 patients, and 108 were case reports. In the 22 selected studies, comprising a total number of 12050 patients, an overall rate of GIST-associated neoplasias of 20% could be calculated. Most second neoplasias were found in the gastrointestinal tract (32%) and in the male and female urogenital tract (30%). The specific risk scores of GISTs associated with other tumors were significantly lower than those without associated neoplasias. CONCLUSION: In this first systematic review, we could confirm previously reported findings of a more than coincidental association between GIST and other neoplasias. The question whether there is an underlying causal association will need further investigation. Our data suggest that even GIST with a very low risk of disease progression should prompt screening for second neoplasia and subsequent frequent controls or extended staging.

Risk of Ovarian Malignancy in Patients Undergoing Radical Cystectomy for Bladder Cancer.

OBJECTIVE: To determine whether there is an increased risk of ovarian cancer in women undergoing radical cystectomy (RC) for bladder cancer using a large population-based data source. Current American Urologic Association guidelines suggest removal of ovaries during RC in women with bladder cancer, presumably to mitigate the risk ovarian cancer. However, recent data have demonstrated an increased risk of all-cause mortality, cardiovascular disease, osteoporosis, cognitive impairment, and diminished sexual function in some populations of women after oophorectomy. METHODS: We queried the surveillance, epidemiology and end results (SEER) database for all women with a diagnosis of primary bladder cancer who underwent RC between 1998 and 2010. Patients with concurrent or subsequent primary ovarian cancer were then identified using the SEER multiple primaries dataset. Multiple primary standardized incidence ratio was calculated as an estimate of the relative risk of a concurrent or subsequent ovarian malignancy using SEER*Stat software. RESULTS: A total of 1851 women met inclusion criteria for analysis. Of this population, 221 (11.9%) women developed a subsequent nonbladder malignancy, of which 2 (0.11%) women developed subsequent ovarian cancer during the observation period. Multiple primary standardized incidence ratio for development of an ovarian malignancy was 2/4 (0.50). CONCLUSION: The risk of concurrent or subsequent ovarian malignancy in women undergoing RC for bladder cancer is very low. Therefore, oophorectomy at the time of RC may be obviated in order to mitigate the undue risk of cardiovascular disease, osteoporosis, cognitive impairment, and diminished sexual function.

Skin protection behaviour and sex differences in melanoma location in patients with multiple primary melanomas.

BACKGROUND/OBJECTIVES: Previous studies have shown that sunscreen usage, sun-protection measures and self-examination rates in patients with single primary melanomas (SPM) are similar to that in the general population. This study hypothesises that these rates would be different in a population with multiple primary melanomas (MPM). We further hypothesise that there would be a sex difference in melanoma location in patients with MPM. The objectives of this study were to determine skin protection measures, self-examinations and melanoma location in a cohort of patients with MPM. METHODS: A survey was conducted on 137 patients with MPM examining their sun-protection measures, skin self-examination rates and medical and phenotypic characteristics. These data were combined with a review of their medical records to examine the patients' skin cancer history. RESULTS: Patients with MPM had higher rates of skin self-evaluation (74% vs 22%), sunscreen usage (70% vs 45%) and other sun-protection measures (95% vs 46%) than has been published for patients with a history of a SPM. We have also shown that women have a higher risk of developing melanomas on their arms (p < 0.01) and lower legs (p < 0.05) than men. CONCLUSIONS: This report showed the rates of skin self-examination, sunscreen usage and other sun-protection methods in patients with MPM is higher than in studies of patients with SPM. It also highlighted sex differences in terms of melanoma location for patients with MPM. Further studies to examine the cause of the differences in these forms of protective behaviour could help improve the utilisation of these important preventative measures in all patients.

Distinguishing synchronous from metachronous manifestation of distant metastases: a prognostic feature in differentiated thyroid carcinoma.

AIM: Distant metastasis has a negative impact on survival in differentiated thyroid carcinoma (DTC). The timing of this manifestation, however, is of unknown prognostic relevance. The aim of this retrospective study was to investigate the potential significance of discriminating synchronous versus metachronous distant metastases (SDM vs. MDM) for the outcome of patients with DTC. METHODS: We retrospectively analyzed a consecutive cohort of n = 89 patients with distant metastases of DTC (43 with follicular, 46 with papillary DTC histology; mean age 52.6 ± 17.7 years) undergoing radioiodine treatment at our institution. All patients were treated with the same protocol consisting of ablative radioiodine therapy (RIT, 3.7 GBq) and one post-ablation treatment after 3 months (3.7-11.1 GBq). Further cycles of RIT were administered for recurrent, progressive or newly developed metastatic disease. We distinguished 2 types of distant metastases according to the time of manifestation: SDM (within ≤12 months after DTC diagnosis) and MDM (occurring >12 months after diagnosis). Tumor-related survival was analyzed using the Kaplan-Meier method. Uni- and multivariate analyses including the Cox proportional hazards model were performed with a significance level of p < 0.05. RESULTS: The mean follow-up period was 13.8 ± 1.2 years. SDM were present in 49 (55.1 %), MDM in 40 (44.9 %) patients. MDM were associated with shorter tumor-related survival (p = 0.002). 5-year and 10-year survival rates were 68.5 % and 34.8 % for MDM, and 84.3 % and 66.9 % for SDM, respectively. Within both age subgroups of <45 and ≥45 years, SDM were also linked with longer survival. No effect on tumor-related survival was found for the co-variables sex, lymph node metastases and histologic type. CONCLUSION: Distinguishing synchronous from metachronous manifestation of distant metastases may add an important prognostic feature to risk stratification in DTC, as proven metachronous appearance is associated with impaired survival.

Bilateral testicular germ cell tumors in patients treated for clinical stage I non-seminoma within two risk-adapted SWENOTECA protocols.

BACKGROUND: A contralateral tumor occurs in 3.5-5% of men diagnosed with testicular germ cell cancer (TGCC). Biopsy of the contralateral testis may detect intratubular germ cell neoplasia ITGCNU, a precursor of TGCC. Biopsy of the contralateral testis to detect ITGCNU is controversial. If adjuvant chemotherapy (ACT) protects against bilateral cancer is debated. MATERIAL AND METHODS: A total of 1003 patients with clinical stage I (CS I) non-seminomatous testicular germ cell cancer (NSGCT) were included in two prospective, population-based protocols. Fifteen patients were excluded. Treatment was either adjuvant chemotherapy (n = 494), or surveillance (n = 494). Contralateral testicular biopsy was recommended for all patients, but was performed only in 282 patients. In case of ITGCNU radiotherapy (RT) to 16 Gy was recommended. RESULTS: During a follow-up of 8.3 years, 31 (3.6%) patients developed contralateral TGCC. ITGCNU was detected in 3.2% (9/282) of biopsied patients. The incidence of bilateral TGCC was similar following ACT, 2.5% (11/494), and surveillance, 3.4% (13/494), p = 0.41. Young age was a risk factor for metachronous TGCC (HR 0.93; 95% CI 0.88-0.99, p = 0.02). In total 2.2% (6/273) of patients without ITGCNU in the biopsy developed contralateral TGCC. One irradiated patient developed contralateral cancer, and one developed contralateral tumor before RT was given. CONCLUSION: ACT did not reduce the incidence of contralateral TGCC. Young patients had the highest risk of developing contralateral TGCC. The proportion of false negatives biopsies was higher than reported in earlier trials, but this may in part be related to patient selection, single biopsies and lack of mandatory immunohistochemistry.

Increasing skin cancer incidence in young, affluent, urban populations: a challenge for prevention.

BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common cancer in white people, but is registered inconsistently by population-based registries. OBJECTIVES: To analyse the changing profile of NMSC in a national population, to interpret evolving patterns of sun exposure and to recommend measures to reduce risk. METHODS: We analysed trends in the demographic, clinical and socioeconomic profile of > 50 000 cases of NMSC registered between 1994 and 2011 by the Irish National Cancer Registry, which aims to register all episodes of NMSC in the Irish population to a high degree of completeness. RESULTS: The incidence of cutaneous basal cell (BCC) and squamous cell carcinoma (SCC) was stable from 1994 to 2002, but increased significantly (BCC more than SCC) in the subsequent decade. The largest relative increases in the incidence of BCC were in younger populations and in clothed body sites. The incidence of both cancers was lower in rural areas. Incidence of BCC and, to a lesser extent, of SCC, increased with increasing affluence in urban, but not in rural, areas. CONCLUSIONS: Recent increases in skin cancers on the trunk and limbs in younger people appear to be related to increasing affluence and consequent leisure-related, episodic sun exposure. This population is at high risk of subsequent skin cancers throughout life and will need active surveillance. As preventive programmes are cost-effective in lowering the incidence of NMSC, they should be targeted at leisure exposure in young people. The recording of consistent international data on NMSC should also be a priority.

Impact of a complex nutraceutical supplement on primary tumour formation and metastasis in Trp53+/- cancer-prone mice.

A complex dietary supplement designed to impact multiple mechanisms associated with aging and cancer reduced overall tumorigenesis in cancer-prone heterozygous Trp53+/- mice by ~30% (P < 0.018). Carcinomas were reduced by 67% (P < 0.006). Remarkably, metastasis (a leading cause of cancer mortality) was undetectable in treated animals (P < 0.004), and the occurrence of multiple primary tumours was reduced by 74% (P < 0.012). Reduction of pulmonary adenocarcinoma by 62% (P < 0.021) was of particular note given that lung cancer is the second leading cause of death in humans. Tumours showed pronounced age-related expression in untreated animals older than 600 days. Benefits of treatment only emerged in these later ages, suggesting that the supplement acted on mechanisms common to aging and cancer. The supplement was administered daily on bagel bits that were usually eaten within minutes by the mice. Although longevity was not statistically different between treatments, longevity was strongly related to the compliance of mice in eating the supplement. Linear regression revealed a strong positive relationship between the proportion of supplement eaten and the longevity of mice within the treatment group (P < 0.0001).

Cetuximab for treatment of advanced squamous cell carcinoma in solid organ transplant recipients.

Survival of solid organ transplant patients has been prolonged, leading to increased incidence of non-melanoma skin cancers. Metastatic squamous cell carcinoma is an increasing problem in these patients. This paper reviews the evidence available for the treatment of advanced squamous cell carcinoma with the epidermal growth factor receptor inhibitor, cetuximab.

[Pigmentary lesions in patients with increased DNA damage due to defective DNA repair]. / Lésions pigmentaires et maladies de la réparation de l'ADN.

The occurrence of abnormally pigmented skin lesions is a common phenomenon and often associated with the influence of ultraviolet radiation (UV) and other sources of DNA damage. Pigmentary lesions induced by UV radiation and other sources of DNA damage occur in healthy individuals, but human diseases with defective DNA repair represent important models which allow the investigation of possible underlying molecular mechanisms leading to hypo- and hyperpigmentations. There are several hereditary diseases which are known to go along with genetic defects of DNA repair mechanisms comprising Xeroderma pigmentosum (XP), Cockayne syndrome (CS), Trichothiodystrophy (TTD), Werner syndrome (WS), Bloom syndrome (BS), Fanconi anemia (FA) and Ataxia telangiectasia (AT). These diseases share clinical characteristics including poikilodermatic skin changes such as hypo-and hyperpigmentation. Since UV radiation is the most common source of DNA damage which can cause pigmentary lesions both in healthy individuals and in patients with genetic deficiency in DNA repair, in the present article, we focus on pigmentary lesions in patients with XP as an example of a disease associated with genetic defects in DNA repair.

[BRCA1- and BRCA2 mutations: Clinical management of patients with hereditary breast and ovarian cancer]. / BRCA1- und BRCA2-Genmutationen: Klinische Konsequenzen beim vererbbaren Brust- und Eierstockkrebs.

BACKGROUND: In total, 5-10% of all breast cancer cases are related to gen mutations. In most cases a mutation in the BRCA1-gen and BRCA2-gen is responsible for insufficient repair of DNA damages that cause breast and ovarian cancer. CLINICAL MANAGEMENT: In patients carrying BRCA1-mutation the risk for developing breast and ovarian cancer is 87% and 40% as well as 47% and 20% for those carrying a BRCA2-mutation. Women at hereditary risk should be informed about existing recommendations for surveillance. Primary prevention of breast and ovarian cancer including prophylactic surgery (bilateral salpingoophorectomy and bilateral mastectomy) should be explained to mutation carriers. The issue of oral antihormonal therapy for prevention of breast cancer should be addressed. Psycho-social support should be offered to mutation carriers. CONCLUSIONS: The clinical management of BRCA1 and BRCA2-mutation carriers is very challenging and should be done in centres specialized in this issue.

[Colonoscopic screening of asymptomatic individuals with a family history of colorectal cancer]. / Screening-ul colonoscopic la persoane asimptomatice cu istoric familial de cancer colorectal.

BACKGROUND AND AIMS: First-degree relatives of colorectal cancer (CRC) patients are at increased risk for developing colorectal neoplasm. The aim of our study was to evaluate the use of total colonoscopy as the screening test in asymptomatic individuals with a family history of colorectal cancer. MATERIAL AND METHOD: Colonoscopy was performed in 125 asymptomatic individuals (64 men and 61 women; mean age 51.7 +/- 11.5 years, range 24-77 years) who had one or two first-degree relatives with CRC. RESULTS: Forty-five colorectal lesions were found in 36 subjects (28.8%): one (0.8%) adenocarcinoma, and 44 polyps (31 adenomas; 13 hiperplasic) (28.0%). The cecum was intubated in 96% of cases, and the procedure was generally well tolerated without complications. CONCLUSIONS: Total colonoscopy is a useful and safe screening procedure for the examinations of asymptomatic individuals with a family history of CRC.

Multiple primary cancer: an increasing health problem. Strategies for prevention in cancer survivors.

This study was set to look for associations between the sites of the first and subsequent tumours in patients with multiple primary cancer (MPC) diagnosed from 1975 to 2002 in the reference hospital of a Spanish northern region, and propose prevention strategies. Patient and tumour variables were measured. Crude and standardized incidence rates per 100 000 inhabitants were obtained, and the association between MPC incidence and time was analysed by means of lineal regression. Relative risks were calculated to analyse associations between tumour sites. A total of 2737 MPC cases were registered (male/female ratio = 2). The percentage of MPC with respect to the total cancer increased from 1.78% in the 1975-1979 period to 7.08% in the 2000-2002 period (R(2) = 0.92; P = 0.003). Great increase of incidence by time was found (R(2) = 0.90; P = 0.004). Breast, prostate and bladder cancers increase risk of second tumour in female genital organs [RR 4.78 (3.84-5.93)], urinary system [RR 3.69 (2.89-4.69)] and male genital organs [RR 3.76 (2.84-4.69)] respectively. The MPC incidence is increasing. Interventions for MPC prevention, according to the European Code against Cancer, should be implemented early after the first cancer principally if patients suffer breast, bladder, prostate, larynx and colon cancers.

Ovarian pathology in risk-reducing salpingo-oophorectomies from women with BRCA mutations, emphasizing the differential diagnosis of occult primary and metastatic carcinoma.

Risk-reducing salpingo-oophorectomy (RRSO) is an effective prophylactic procedure for women with mutations in BRCA1 or BRCA2 genes, both of which confer an increased lifetime risk for ovarian, tubal, peritoneal, and breast cancer. In addition to lowering this risk, RRSO also offers the opportunity to detect occult early-stage fallopian tube or ovarian carcinoma. The differential diagnosis of occult tubal/ovarian cancer includes a spectrum of benign tubal and ovarian alterations and also occult metastatic breast cancer, although only rare cases of the latter have been reported in RRSO. Neoadjuvant breast cancer chemotherapy may contribute to diagnostic difficulty due to treatment-induced cytologic alterations. With the aim of elucidating features which may help with differential diagnosis, this study reports the incidence and pathologic features of benign ovarian alterations, benign ovarian tumors, and occult primary and metastatic malignancies in prophylactic oophorectomies from 108 women with a BRCA mutation and from 35 women with other strong risk factors for hereditary breast/ovarian carcinoma. We direct particular emphasis on morphologic features of primary ovarian lesions that may mimic occult metastatic breast cancer. We also evaluate histologic alterations due to neoadjuvant breast cancer chemotherapy in the ovary and fallopian tube of patients who received such treatment immediately preceding RRSO. Comparison is made to ovarian metastases of breast cancer in our hospital-based population of breast cancer patients, none of whom underwent RRSO. Overall, 69% of RRSO patients had a personal history of breast cancer. Neoadjuvant breast cancer chemotherapy was administered in 15%. Occult primary carcinoma occurred in 7 (6.5%) BRCA patients (5 in fallopian tube, 1 in fallopian tube and ovary, 1 in ovary). Ovarian metastasis of breast cancer occurred in 1 (1%) BRCA patient undergoing RRSO and in up to a similar proportion (0.8%) of the hospital-based population of breast cancer patients. The metastasis in the RRSO patient was clinically occult, unilateral, 0.2 cm, and demonstrated mild atypia without mitoses. Abundant foamy, vacuolated cytoplasm due to neoadjuvant chemotherapy exposure was notable. In contrast, ovarian metastases in the non-RRSO population were all clinically detected, bilateral, large, and exhibited well-developed malignant cytologic features. None of the normal cell types in the ovary or tube demonstrated any cytologic alterations in RRSO patients who received neoadjuvant chemotherapy. The main morphologic mimics of metastasis with superimposed chemotherapy-induced alterations in RRSO were stromal hyperthecosis (n=8), nodular hyperthecosis (n=2), adrenal rests (n=3), hilus cell nodules (n=43), and hilus cell hyperplasia (n=4). Occult primary ovarian carcinoma was reliably distinguished from ovarian metastases of breast cancer by WT-1+, p53+, mammaglobin-, GCDPF-immunoprofile. These results demonstrate that evaluation of RRSO specimens requires awareness of a spectrum of ovarian lesions which may mimic occult primary or metastatic carcinoma; awareness of the masquerading effects of neoadjuvant chemotherapy; and awareness of the potential morphologic differences between occult metastatic breast cancer in RRSO and non-RRSO specimens.

[Multiple skin cancers in a patient treated with hydroxyurea]. / Multiple kutane Neoplasien nach Therapie mit Hydroxyurea.

A 62-year-old patient treated for 9 years with hydroxyurea for chronic myeloproliferative disease developed multiple cutaneous neoplasms. Hydroxyurea minimizes DNA synthesis via inhibition of the enzyme ribonucleotide reductase and is used to treat hematological malignancies. The most important and severe side-effect is a dose-dependent myelodepression. An association with multiple skin tumors has been reported. The presented case emphasizes this potential risk of hydroxyurea therapy. Continuous dermatologic monitoring of patients treated with hydroxyurea is recommended.

New pharmacological strategies against metastatic spread.

Although metastatic spread is the most frequent cause of death in cancer patients, there are very few drugs specifically targeting this process. Bases for a new antimetastatic drug discovery strategy are weak because a great number of unknowns characterize the complete understanding of the metastatic cascade mechanisms. Moreover, the current experimental models are too simplistic and do not account for the complexity of the phenomenon. Some targets have been identified but too few are validated. Among them, the metastasis suppressor genes seem to be the most promising. In spite of this, during recent years, a dozen of molecules, which fulfil the definition of a specific metastatic drug that inhibits the metastases without altering the growth of the primary tumour (which can be eradicated by surgery), have been identified and assessed for the proof of the concept. The continuation of this effort would benefit in terms of efficiency, if the objectives were defined more precisely. It is particularly important to distinguish molecules that prevent spread of the metastatic cells of the early-stage primary tumour from the ones which induce a regression of the established metastases or to inhibit the transition from disseminated occult tumour cells to dormant micrometastasis. This second goal is a priori more relevant in the current clinical setting where the detection of early metastatic spread is very difficult, and therefore would call for greater effort on the part of the scientific community.