Uncovering the clinical relevance of unclassified variants in DNA repair genes: a focus on BRCA negative Tunisian cancer families.

Introduction: Recent advances in sequencing technologies have significantly increased our capability to acquire large amounts of genetic data. However, the clinical relevance of the generated data continues to be challenging particularly with the identification of Variants of Uncertain Significance (VUSs) whose pathogenicity remains unclear. In the current report, we aim to evaluate the clinical relevance and the pathogenicity of VUSs in DNA repair genes among Tunisian breast cancer families. Methods: A total of 67 unsolved breast cancer cases have been investigated. The pathogenicity of VUSs identified within 26 DNA repair genes was assessed using different in silico prediction tools including SIFT, PolyPhen2, Align-GVGD and VarSEAK. Effects on the 3D structure were evaluated using the stability predictor DynaMut and molecular dynamics simulation with NAMD. Family segregation analysis was also performed. Results: Among a total of 37 VUSs identified, 11 variants are likely deleterious affecting ATM, BLM, CHEK2, ERCC3, FANCC, FANCG, MSH2, PMS2 and RAD50 genes. The BLM variant, c.3254dupT, is novel and seems to be associated with increased risk of breast, endometrial and colon cancer. Moreover, c.6115G>A in ATM and c.592+3A>T in CHEK2 were of keen interest identified in families with multiple breast cancer cases and their familial cosegregation with disease has been also confirmed. In addition, functional in silico analyses revealed that the ATM variant may lead to protein immobilization and rigidification thus decreasing its activity. We have also shown that FANCC and FANCG variants may lead to protein destabilization and alteration of the structure compactness which may affect FANCC and FANCG protein activity. Conclusion: Our findings revealed that VUSs in DNA repair genes might be associated with increased cancer risk and highlight the need for variant reclassification for better disease management. This will help to improve the genetic diagnosis and therapeutic strategies of cancer patients not only in Tunisia but also in neighboring countries.

Association between epidemiological and clinico-pathological features of breast cancer with prognosis, family history, Ki-67 proliferation index and survival in Tunisian breast cancer patients.

Breast cancer has different epidemio-clinical characteristics in Middle East and North-African populations compared to those reported in the Western countries. The aim of this study is to analyze the epidemiological and clinico-pathological features of breast cancer in Tunisia and to determine prognostic factors with special interest to family history, Ki-67 proliferation index and comorbidity. We retrospectively reviewed epidemiological and clinico-pathological data from patients' medical records, treated in the Medical Oncology Department at Abderrahmane Mami Hospital, in the period 2011-2015. Data has been collected on 602 breast cancer patients and analyzed using SPSS software V.23.0. Our study showed high fractions of young breast cancer patients and cases with dense breasts. The most prevalent comorbidities observed in the studied cohort were cardiovascular diseases and diabetes. Familial breast cancer was found in 23.3% of cases and was associated with younger age at diagnosis (p<0.001) and advanced stage (p = 0.015). Ki-67 index >20% was significantly associated with early age at diagnosis, lymph node involvement (p = 0.002), advanced tumor grade (p<0.001) and high risk of relapse (p = 0.007). Ki-67 cut-off 30% predicted survival in luminal cases. Survival was worse in patients with triple negative breast cancer compared to non-triple negative breast cancer, inflammatory breast cancer compared to non-inflammatory breast cancer, moderately to poorly differentiated tumors compared to well-differentiated tumors and with positive lymph nodes compared to pN0 (p<0.05). Our study showed new insights into epidemiological and clinico-pathological characteristics of breast cancer that are not well explored in Tunisian population. Considering our findings along with the implementation of electronic health record system may improve patient health care quality and disease management.

Identification of Eleven Novel BRCA Mutations in Tunisia: Impact on the Clinical Management of BRCA Related Cancers.

BACKGROUND: Breast cancer is the world's most common cancer among women. It is becoming an increasingly urgent problem in low- and middle-income countries (LMICs) where a large fraction of women is diagnosed with advanced-stage disease and have no access to treatment or basic palliative care. About 5-10% of all breast cancers can be attributed to hereditary genetic components and up to 25% of familial cases are due to mutations in BRCA1/2 genes. Since their discovery in 1994 and 1995, as few as 18 mutations have been identified in BRCA genes in the Tunisian population. The aim of this study is to identify additional BRCA mutations, to estimate their contribution to the hereditary breast and ovarian cancers in Tunisia and to investigate the clinicopathological signatures associated with BRCA mutations. METHODS: A total of 354 patients diagnosed with breast and ovarian cancers, including 5 male breast cancer cases, have been investigated for BRCA1/2 mutations using traditional and/or next generation sequencing technologies. Clinicopathological signatures associated with BRCA mutations have also been investigated. RESULTS: In the current study, 16 distinct mutations were detected: 10 in BRCA1 and 6 in BRCA2, of which 11 are described for the first time in Tunisia including 3 variations that have not been reported previously in public databases namely BRCA1_c.915T>A; BRCA2_c.-227-?_7805+? and BRCA2_c.249delG. Early age at onset, family history of ovarian cancer and high tumor grade were significantly associated with BRCA status. BRCA1 carriers were more likely to be triple negative breast cancer compared to BRCA2 carriers. A relatively high frequency of contralateral breast cancer and ovarian cancer occurrence was observed among BRCA carriers and was more frequent in patients carrying BRCA1 mutations. CONCLUSION: Our study provides new insights into breast and ovarian cancer genetic landscape in the under-represented North African populations. The prevalence assessment of novel and recurrent BRCA1/2 pathogenic mutations will enhance the use of personalized treatment and precise screening strategies by both affected and unaffected North African cancer cases.

Identification of BRCA2 Cis Double Heterozygous Breast Cancer Cases Using Whole Exome Sequencing: Phenotypic Expression and Impact on Personalized Oncology.

BRCA1 and BRCA2 are the most commonly mutated breast cancer susceptibility genes that convey a high risk of breast and ovarian cancer. Most BRCA1 or BRCA2 mutation carriers have inherited a single heterozygous mutation. In recent years, very rare cases with biallelic or trans double heterozygous mutations on BRCA1 and or BRCA2 have been identified and seem to be associated with distinctive phenotypes. Given that this genotype-phenotype correlation in cancer predisposing hereditary conditions is of relevance for oncological prevention and genetic testing, it is important to investigate these rare BRCA genotypes for better clinical management of BRCA mutation carriers. Here we present the first report on Cis double heterozygosity (Cis DH) on BRCA2 gene identified using Whole exome sequencing (WES) in a Tunisian family with two BRCA2 mutations namely: c.632-1G>A and c.1310_1313DelAAGA that are both reported as pathogenic in ClinVar database. Subsequent analysis in 300 high-risk Tunisian breast cancer families detected this Cis double heterozygous genotype in 8 additional individuals belonging to 5 families from the same geographic origin suggesting a founder effect. Moreover, the observed Cis DH seems to be associated with an early age of onset (mean age = 35.33 years) and severe phenotype of the disease with high breast cancer grade and multiple cancer cases in the family. The identification of unusual BRCA genotypes in this Tunisian cohort highlights the importance of performing genetic studies in under-investigated populations. This will also potentially help avoiding erroneous classifications of genetic variants in African population and therefore avoiding clinical misdiagnosis of BRCA related cancers. Our findings will also have an impact on the genetic testing and the clinical management of North African breast cancer patients as well as patients from different other ethnic groups in regard to several emerging target therapies such as PARP inhibitors.

A review of the international early recommendations for departments organization and cancer management priorities during the global COVID-19 pandemic: applicability in low- and middle-income countries.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new virus that has never been identified in humans before. COVID-19 caused at the time of writing of this article, 2.5 million cases of infections in 193 countries with 165,000 deaths, including two-third in Europe. In this context, Oncology Departments of the affected countries had to adapt quickly their health system care and establish new organizations and priorities. Thus, numerous recommendations and therapeutic options have been reported to optimize therapy delivery to patients with chronic disease and cancer. Obviously, while these cancer care recommendations are immediately applicable in Europe, they may not be applicable in certain emerging and low- and middle-income countries (LMICs). In this review, we aimed to summarize these international guidelines in accordance with cancer types, making a synthesis for daily practice to protect patients, staff and tailor anti-cancer therapy delivery taking into account patients/tumour criteria and tools availability. Thus, we will discuss their applicability in the LMICs with different organizations, limited means and different constraints.

Once-a-day fractionated total-body irradiation: A regimen tailored to local logistics in allogeneic stem cell transplantation for acute lymphoblastic leukemia.

AIM: The objective of the study was to estimate the cumulative incidence (CI) of relapse, relapse-free survival (RFS) and overall survival (OS) in ALL patients after a once-a-day fractionated TBI (F-TBI) regimen with 9.9 Gy. The secondary objectives were evaluation of short and long-term toxicity and non-relapse mortality (NRM). BACKGROUND: Total body irradiation (TBI), as a part of the conditioning regimen before allogeneic stem cell transplantation (ASCT) for acute lymphoblastic leukemia (ALL), allows disease control by eradicating residual blast cells in the transplant recipient. MATERIALS AND METHODS: Retrospective study conducted in patients with ALL who received between March 2003 and December 2013 a conditioning regimen with F-TBI and chemotherapy. Irradiation was delivered with 3.3 Gy once-a-day for three consecutive days. RESULTS: Eighty-seven patients were included. The median age was 19 years (range: 5-49 years). The 3-year CI of relapse was 30%. The estimated 3-year RFS and OS were 54% and 58%, respectively. Cumulative incidence of acute graft-versus-host disease (aGVHD) grade II-IV and chronic GVHD (cGVHD) was 31% and 40%, respectively. Interstitial pneumonitis was observed in 2 patients. The 3-year CI of NRM was 16%. In multivariate analysis, cGVHD was associated with a lower CI of relapse (RR = 0.26, 95% CI: 0.07-0.95, p = 0.04). High-risk cytogenetics was associated with a lower RFS (RR = 2, 95 CI: 1.04-3.84, p = 0.03). Grade II-IV aGVHD was an independent predictor of higher CI of NRM (RR = 6.7, 95% CI: 1.4-31.7, p = 0.02). CONCLUSIONS: Once-a-day F-TBI regimen is effective, safe and practical in patients who underwent ASCT for ALL.

Female oncologists in the Middle East and North Africa: progress towards gender equality.

BACKGROUND: Female doctors are increasingly choosing oncology as a career while they are still under-represented in leadership positions globally. The European Society of Medical Oncology has recently surveyed its members regarding gender equality in the work place. Limited data are available from the Middle East. The aim of our study was to survey female oncologists practicing in the Middle East to identify common challenges and suggest areas for improvement. METHODS: A cross-sectional survey was distributed among female participants attending the annual Lebanese Society of Medical Oncology meeting in March 2018, and in the Pan-Arab annual meeting in April 2018. The questionnaire used included questions assessing sociodemographic characteristics, involvement in leadership and academic positions and the impact of career on family life. RESULTS: Overall, 88 questionnaires were collected from women practicing all over the Middle East. 59% reported that a male doctor was responsible for the work team; however, 57% covered a managerial or leadership role within their job. 64% of the female oncologists believed that their gender had at least moderate, significant and even major impact on their career. Participants reported that their careers have a considerable impact on their relationship with friends and social networking (49%) and their family and marriage (44%). 58% report having problems with finding balance between work and family, and 50% find barriers to attend international meetings. Several ways to improve were suggested, 56% voted for offering development and leadership training specifically women, 45% suggested implementing a flexible work schedule. CONCLUSION: In what is considered a male dominant environment, gender equality according to female oncologists working in the Middle East, is very comparable to the world data provided. Several strategies have been identified to continue progress in this domain with the aim to improve academic leadership opportunities and work-life balance for all.

Rare Case of a Well-Differentiated Paratesticular Sarcoma of the Spermatic Cord in a 60-Year-Old Patient.

Introduction. Liposarcomas are tumors that occur mostly in the retroperitoneum. Of all liposarcomas only 3 to 7% are found in the paratesticular region. The spermatic cord is the main site of origin in these cases. The patients ages range from 50 to 60 years. This malignant disease can result in a loss of fertility aside from life-threatening sequelae. Case. We present a case of a liposarcoma of the paratesticular region. A 60-year-old man was referred with a painless mass in the scrotum and the right inguinal region. The patient underwent surgery and the mass was removed along with the right testis, the spermatic cord, and the soft tissues to the internal inguinal ring. Histopathological examination found a well-differentiated liposarcoma of 80⁎80 mm. The surgical margins were negative. The adjuvant treatment consisted in radiation therapy of the right inguinoscrotal area to the dose of 54 Gray, 2 Gy per session, 5 times a week. Conclusion. Paratesticular liposarcomas are rare tumors. Surgery with large margin resections was the main treatment in all reported cases. The adjuvant treatment is still unclear especially when the surgical margins are negative. The main factor that indicated this adjuvant treatment was the size of the tumor and the histologic subtype.

Gastric metastasis of bilateral breast cancer.

Breast cancer is the most common malignancy in women. The most frequent metastatic sites are lung, bone, liver and brain. On the other hand, gastric metastases are rare. Synchronous bilateral breast cancer (SBBC) occurs rarely. Lobular carcinoma is the histological type most often associated with bilateral breast carcinomas and gastric metastases. We made a retrospective study including four patients followed in the Salah Azaiez Institute, for a bilateral breast cancer with gastric metastases. We analyzed the epidemiological, anatomoclinical and therapeutic particularities of this rare entity. Symptoms were unspecific. The diagnosis of gastric metastasis of the SBBC was confirmed by a histopathological examination of an endoscopic biopsy. The median age was 46.2 years (range, 36-51 years) and the median time until the gastric involvement was 19 months (range, 0-41 months). None of patients had a surgical treatment for the gastric location. All Patients received at least one line of chemotherapy and radiotherapy. Median survival following the detection of gastric involvement was 22 months (range, 1-56 months). Gastric metastases from breast cancer are rare and frequently associated with other distant metastasis. Symptoms are unspecific and endoscopy may not be contributive. Therefore, gastric involvement is underestimated. Lobular infiltrating carcinoma (LIC) is the most histological type incriminated in its occurrence. The supply of immunohistochemistry is crucial to distinguish between primary or metastatic gastric cancer.

Brachytherapy of Uveal Melanomas with Ruthenium-106 Plaques

Background: Brachytherapy is the most commonly used conservative treatment for the uveal melanoma. The aim of this study was to evaluate therapeutic results of Ruthenium-106 plaque brachytherapy in the management of localized uveal melanoma cases. Methods: We reviewed retrospectively the clinical records of all patients treated in our department for an uveal melanoma, undergoing Ruthenium-106 plaque brachytherapy, from January 1996 to December 2015. We focused on clinical features, therapeutic characteristics, local and distant tumor control and side effects. Results: Nineteen patients were enrolled in our study. Mean age was 56.2 years (28-79) and the sex ratio was 1.37:1 males to females. Diagnosis was made on the basis of ophthalmological clinical examination, angiography, ultrasound and/or magnetic resonance. Median tumor diameter was 9.7 mm (6-13) and median thickness 4.4 mm (2.5- 8). The dose of Ruthenium-106 plaque brachytherapy prescribed to the apex of each tumor was 70 Gy in all cases. The median radiation dose to the sclera surface was 226.4 Gy (range: 179.6­342.3) and the median total application time 115.2 hours (range: 27 to 237). After a median follow-up of 61.5 months, local control was achieved in 17 patients (89%): 16 demonstrated a partial tumor response and 1 tumor stabilization. Two patients suffered local progression leading to enucleation, one dying of hepatic metastasis. Radiation-induced complications were cataracts in 3 cases and vitreal hemorrhage in 2. Conclusion: Ruthenium-106 plaque brachytherapy is an efficient treatment for localized uveal melanoma, offering good local control with low toxicity.

Glioblastoma in Tunisia: A retrospective study about 41 cases.

BACKGROUND: Glioblastoma (GB) is the most common and lethal primary brain tumor in adults representing 25% of primary brain tumors in adults. The objective of our study was to report the epidemiologic, clinical and therapeutic features of GB in Tunisia. METHODS: Our retrospective study included 41 patients with histologically confirmed GB treated between 2006 and 2012 at the medical oncology departments of Abderrahmane Mami hospital in Ariana and the military hospital in Tunis. RESULTS: Median age was 54 years (13 to 72 years) and sex-ratio was 2.3. Karnofsky performance status (KPS) was <70% in 31.7% of cases, while Recursive partitioning analysis radiation therapy oncology group (RTOG-RPA) classification was III in 11 (26.8%), IV in 19 (46.3%), V in 10 (24.3%) and VI in 1 (2.4%) cases. Complete resection (CR) was achieved in 29 patients (70.7%), partial resection (PR) or tumor debulking in 5 patients (12.2%) and biopsy alone (BA) in 7 patients (17.1%). All patients received brain radiotherapy (RT) at a dose of 60 Gy combined with concurrent temozolomide (TMZ). Nineteen patients (46.3%) received adjuvant TMZ, 8 of them completed 6 cycles. Median overall survival (OS) was 12 months (2 to 56 months). Six, 12, 18 and 24-months OS rates were 84.6%, 57.6%, 35.4% and 20.7%, OS being correlated to age, KPS, RPA and quality of resection. CONCLUSION: Our retrospective study is the first African GB series. Despite it included predominantly poor prognosis patients with impaired neurocognitive function and adjuvant treatment discontinuation, our median OS was comparable to Stupp.

Nasopharyngeal cancer (NPC) around the Mediterranean area: standard of care.

Mediterranean area (MA) represents a zone of intermediate incidence (1-5/100,000) for NPC, the highest frequency being observed in North Africa (NA) where it is characterized by a bimodal age repartition due to a first adolescence peak. In MA and NA, NPC remain diagnosed at advanced stages which impact poorly on overall and disease-free survival. It's therapy in MA followed the progresses and standardisation of protocols, based on concomitant chemoradiotherapy (CCRT) alone or preceded by induction chemotherapy (ICT) in advanced (N2-3, T3-4) stages, while localized cases are managed irradiation alone. NPC overall an disease-free survival improved, due to the use of combined chemo and radiotherapy.

Inflammatory breast cancer in Tunisia: epidemiological and clinical trends.

Inflammatory breast cancer (IBC) is characterized by a peculiar geographic distribution in incidence, being described as more common in Tunisia and the region of North Africa. The authors performed a systematic review of published literature on rapidly progressing breast cancer and IBC in Tunisia and analyzed the evolution in epidemiology, clinical presentation, treatment, and therapeutic results. They collected, analyzed, and compared all the indexed Tunisian articles about rapidly progressing breast cancer and IBC since the 1970s opening of the Institut Salah Azaiz Institute in Tunis. In the 1970s, rapidly progressing breast cancer diagnosis was based on the Poussée Evolutive classification (1-3). Since the 1990s, IBC diagnosis has been based on the American Joint Committee on Cancer Poussée Evolutive 3/T4d staging. The authors compared the historical data to the most recent publications in terms of epidemiology, clinical features, treatment, and therapeutic results. The most important historical report of rapidly progressing breast cancer concerned 340 patients, representing 58.5% of a cohort of 581 breast cancer patients collected from 1969 to 1974, including 320 (55.2%) with inflammatory signs, 37(6.5%) with Poussée Evolutive 2, and 283 (48.7%) with Poussée Evolutive 3. Subsequent papers have documented a steady decrease in incidence to the current 5% to 7% T4d/IBC. Since the 1970s, Poussée Evolutive in premenopausal woman has increased from 52.5% to 75%; rural predominance has persisted. The 5-year overall survival reached 28% by the year 2000. The authors' analysis demonstrated a trend of decreasing incidence of IBC diagnoses from 50% to presently <10%, probably related to a combination of factors, including the use of more stringent criteria (Poussée Evolutive 3/T4d) for IBC diagnosis and an improvement in the socioeconomic level of Tunisia.

[Update on medical therapies of nasopharyngeal carcinomas]. / Actualités des traitements médicaux des cancers du nasopharynx.

Nasopharyngeal carcinomas (NPC) are predominantly of undifferentiated type (UCNT or undifferentiated carcinoma of nasopharyngeal type), rare (<1/100,000) and sporadic in occidental countries, but endemic in the Mediterranean area of intermediate incidence (2 to 10/100,000) and highly frequent (>10/100,000) in South East Asia. NPC staging is based on TNM UICC 2002 that has a prognostic and therapeutic orientation impact. Irradiation of the primitive tumor and its extensions remains the standard loco-regional treatment. The recent introduction of primary and concomitant chemotherapy leads to an improvement in terms of overall and disease-free survival, specially for for high-risk-patients (T3-4 and N2-3 disease). Prognosis remain linked to T, N, histologic type and quality of response to chemotherapy and radiotherapy.

Expression of WISP3 and RhoC genes at mRNA and protein levels in inflammatory and noninflammatory breast cancer in Tunisian patients.

Previous studies have shown the expression WISP3 and RhoC in cell lines of inflammatory breast cancer (IBC). The aim in the current study was to compare the expression of both genes, in biopsy samples collected from Tunisian patients with localized or metastatic breast cancer and patients with IBC. We investigated 127 patients enrolled in Salah Azaiez Institute in Tunis. Using the RT-PCR, we showed the phenotype (WISP3-, RhoC+) is significantly associated with IBC tumors, while the (WISP3+, RhoC-)phenotype is mostly associated to non-IBC tumors. The frequencies of these tumor phenotypes are significantly different between these tumor groups (p = 10(- 7); relative risk or RR = 3.25; confidential interval or CI 95% = 1.90-5.53). Immunohistochemical test revealing the presence of WISP3 and RhoC proteins correlates with the expression in the biopsy of their encoding genes as detected by RT-PCR. In conclusion, it appears that WISP3 and RhoC genes expression status defines a molecular signature of IBC.

Inflammatory breast cancer in Tunisia: reassessment of incidence and clinicopathological features.

Inflammatory breast cancer (IBC) is a clinical diagnosis characterized by a peculiar geographic distribution in incidence, being particularly common in Tunisia and the region of North Africa. The peculiar aspects of the disease in this region may provide some insights on the biological characteristics of the disease. We updated and revised the data from our single-institution experience using the more stringent diagnostic criteria of the International Union Against Cancer (UICC) based on the tumor-node-metastasis (TNM) classification. The new analysis included 419 newly diagnosed cases of IBC evaluated between 1975 and 1996 that were subdivided into three groups: group A (118 cases classified as T4d in 1990-1996); group B (175 cases reported as Pev 2 or 3 in 1975-81 and restaged as T4d); and group C (126 cases classified Pev 2 or 3 in 1975-81 and restaged as T4b). The frequency of IBC cases classified as T4d in the various series was 5.7% for group A (118/2,073) and 13.3% for group B (175/1,317), while T4b represented 9% for group C (126/1,317). The analysis demonstrated worse 5-year overall survival rates for groups A and B (8.5% and 11.3%, respectively) compared to group C (25.6%). Interestingly, using a more uniform classification criteria, the incidence of IBC was 5% to 7% compared to previous historical reports of up to 50% of newly diagnosed cases of breast cancer in Tunisia.

[Juvenile granulosa cell tumor of the ovary. A case report]. / Tumeur juvenile de la granulosa ovarienne. A propos d'une observation.

Juvenile granulosa cell tumors of the ovary (JGCTs) are a rare form of neoplasm that makes up less than 5% of ovarians tumors in childhood and adolescence. About 90% are diagnosed in stage I (FIGO) with a favorable prognosis, whereas those at higher stages have a less favorable outecome. The authors describe a juvenile granulosa cell tumor expressed by an early pseudopuberty occurring in a 6 year old child. Clinically, an endocrine syndrome was associated with a pelvic mass. Hyperoestrogenia and serum alphafoetoprotein level were biologically detected. Tumor was localized strictly to the ovary, so conservative surgery was applied and proved sufficient to remove all tumor tissue. Histological examination showed typical microscopic aspect of a juvenile granulosa cell tumor. The patient is well, 14 years after surgery with a normal growth and mental developpment.

[Medulloblastoma with extracentral nervous system metastases: clinical presentation and risk factors]. / Medulloblastoma with extracentral nervous system metastases: clinical presentation and risk factors.

PURPOSE: Extra-central nervous system (extra-CNS) metastases are relatively unknown failure patterns in medulloblastoma. The aim of this study was to analyse epidemiological, clinical and aetiopathological aspects of these extra-CNS localisations. PATIENTS AND METHODS: Extra-CNS metastases were retrospectively identified in patients treated in the department of radiation therapy at Salah-Azaïz institute (ISA) for medulloblastoma. These metastases were diagnosed as extra-CNS for all secondary localisations not related to other tumour aetiology. Aetiopathological aspects are discussed with a literature review. RESULTS: Among 103 patients treated and followed-up in the department of radiation therapy of ISA from 1970 to 1992, 8 developed extra-CNS metastases (7.7%). Age at diagnosis of primitive tumour varied from 3 to 23 years. Sex ratio was 1. Primitive tumour treatment was: complete surgical resection in 4 patients with preoperative cerebrospinal fluid shunting in two, cerebrospinal axis irradiation in 7 patients and a cerebral-limited irradiation in 1. Two patients received chemotherapy for their initial treatment (systemic in one case and intrathecal in the other). The mean free-interval from diagnosis of primitive tumour to extra-CNS metastases was 23 months, varying from 8 to 53 months. These metastases were located in the liver (1 case), cervical lymph nodes (2 cases), bone marrow (1 case) and bone (2 cases). Two patients had multiple metastases: bone and bone marrow (in one), lung, pleura, cervical lymph node and bone localisations (in one). Treatment of these metastases was: chemotherapy in 5 cases, chemotherapy and radiation in one, radiation therapy in one and 2 patients were given only supportive care treatment. All patients died or are in progressive disease in less than one year from the diagnosis of extra-CNS metastases. CONCLUSION: Extra-CNS metastases are not rare and have a poor prognosis. The most commonly involved sites are bone, cervical lymph nodes and bone marrow. A complete work-up at initial diagnosis is recommended to screen early metastases. Literature review showed that histopathologic grading might help to identify groups at risk.