Primary cutaneous sarcomas showing rhabdomyoblastic differentiation

Rhabdomyosarcoma is a rare soft tissue neoplasm most commonly encountered in childhood and adolescence which has a predilection for the head and neck area, the genito-urinary tract and the extremities. Primary cutaneous presentation is extremely unusual and has been rarely reported in the literature. Herein, we describe two cases of rhabdomyosarcoma arising in the dermis of a 9-year-old girl and an 86-year-old man. Clinically, the tumours presented as solitary plaque-like or nodular lesions confined to the skin of the nose and chest wall, respectively. Histologically, the tumour in the first patient corresponded to an embryonal rhabdomyosarcoma. The tumour recurred locally four times, and in the last recurrence, showed features resembling those of malignant 'triton' tumour with fascicles of S-100 protein-positive spindle cells admixed with the rhabdomyoblastic components. The tumour in the second patient corresponded to the solid variant of alveolar rhabdomyosarcoma. Immunohisto-chemical studies in both tumours showed positive labelling for muscle-specific actin, desmin and vimentin. Ultrastructural examination in one case showed clusters of intermediate filaments in the cytoplasm recapitulating abortive sarcomeric structures consistent with rhabdomyoblastic differentiation. Both patients developed repeated recurrences over a period of 2–4 years despite adequate surgical excision, and the second patient had an axillary lymph node metastasis. Primary cutaneous rhabdomyosarcoma should be considered in the evaluation of small 'blue cell' tumours or undifferentiated malignant neoplasms of the skin, and appropriate immunohistochemical studies in conjuction with electron microscopy should be employed for proper evaluation of such lesions.     

Clinical expression and SRY gene analysis in XY subjects lacking gonadal tissue

In several syndromes genetic males lack gonadal tissue. A range of phenotypes are seen, which varies from complete female external genitalia to anorchic subjects with sexual infantilism. Differences in phenotypic expression depend on the stage at which testes degenerated during intrauterine development. Although most cases of these syndromes are sporadic, several instances of familial recurrence suggest a genetic origin. To help elucidate the source, we performed molecular analysis of the complete SRY gene open reading frame in two subjects with true agonadism and in two with anorchia. Our results add to previous findings indicating that molecular defects in SRY are not readily identified as a cause of these syndromes.     

Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood

The Ehlers-Danlos syndromes (EDS) form a clinically and genetically heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, tissue fragility and skin abnormalities. Six subtypes have been well characterized based on clinical features and molecular genetic abnormalities. The arthrochalasia type EDS (formerly types VIIA and B) is characterized by severe generalized joint hypermobility with multiple dislocations including congenital bilateral dislocation of the hips, muscular hypotonia and distinct dysmorphic features. The diagnosis of the arthrochalasia type EDS is of importance in the neonatal period because of consequences of physical disability in later life. However, the differential diagnosis may be difficult because of overlap with other hypermobility syndromes. In addition, the significant hypotonia may direct the physician toward various neuromuscular diagnoses. As patients become older, the hypotonia decreases and facial features become less distinct. In this report, we describe seven patients at different ages. Timing of diagnosis varied from prenatal life to adult age. The diagnosis of EDS type VII was confirmed by biochemical studies or mutation analysis showing characteristic mutations in COL1A1 and COL1A2. These mutations result in skipping of exon 6, which leads to defective collagen synthesis. For physicians treating patients with EDS type VII, achieving mobility for the patient is the greatest challenge and it may be impossible because of recurrent dislocations of nearly all joints in severe cases.     

Concurrent T-cell lymphocytic lymphoma and malignant histiocytosis

A case in which both malignant histiocytosis and T-cell lymphocytic lymphoma occurred together is presented. Examples of malignant histiocytosis-like syndromes associated with lymphoreticular malignancies have been previously reported. Many of these represent reactive haemophagocytic syndromes, probably virally induced. The considerable degree of cytological atypia and frequent mitotic figures seen in the histiocytes in this case were indicative of a true malignant histiocytosis.     

Pseudomyogenic haemangioendothelioma: a case report and overview of a potential diagnostic pitfall

Pseudomyogenic haemangioendothelioma (PHE) is a rare vascular tumour which can arise in skin, soft tissue and bone, posing a diagnostic challenge due to its similar histological appearances to several soft tissue and skin neoplasms. We report an unusual case of PHE with aggressive behaviour and provide an overview of this unique entity, discussing important differential diagnoses and highlighting key histological, immunohistochemical and genetic features which aid in its accurate diagnosis.     

Clinical manifestations of hyper IgE syndromes

Over the last 4 years, three genetic etiologies of hyper IgE syndromes have been identified: STAT3, DOCK8, and Tyk2. All of these hyper IgE syndromes are characterized by eczema, sinopulmonary infections, and greatly elevated serum IgE. However, each has distinct clinical manifestations. Mutations in STAT3 cause autosomal dominant HIES (Job's syndrome), which is unique in its diversity of connective tissue, skeletal, and vascular abnormalities. DOCK8 deficiency is characterized by severe cutaneous viral infections such as warts, and a predisposition to malignancies at a young age. Only one individual has been identified with a hyper IgE phenotype associated with Tyk2 deficiency, which is characterized by nontuberculous mycobacterial infection. The identification of these genetic etiologies is leading to advances in understanding the pathogenesis of these syndromes with the goal of improving treatment.     

Two hits revisited again

INTRODUCTION AND METHODS—Since the concept of the "two hit hypothesis" was introduced over 20 years ago, a wealth of genetic data has accumulated on the mutations found at tumour suppressor loci. Perhaps surprisingly, these data conceal large gaps in our knowledge which genetic and functional studies are beginning to uncover. The "two hit hypothesis" must be updated to take account of this new information.RESULTS AND DISCUSSION—Here, we discuss both the results of recent studies and some of the questions that they highlight. In particular, how valid are conclusions from inherited Mendelian syndromes when applied to sporadic cancers? Why is allelic loss so common and how does it occur? Are the "two hits" random or interdependent? Is abolition of protein function always optimal for tumorigenesis? Can "third hits" occur and, if so, why? How can mismatch repair deficiency and the methylator phenotype be incorporated into the "two hit" hypothesis? We suggest that the "two hit hypothesis" is not fixed but is evolving as our knowledge expands.     

Primitive neuroectodermal tumour of the central nervous system associated with malignant rhabdoid tumour of the kidney: report of a case

Malignant rhabdoid tumour of the kidney is a recently reported tumour presenting in young children. Irrespective of stage and despite intensive chemotherapy these tumours have a poor prognosis, with death usually occurring within a matter of months. A recent report has shown the association of second embryonal tumours of the central nervous system occurring in patients with the renal tumour; most of these second tumours have occurred in the posterior fossa. We report here an infant who presented with a mass in the right groin, showing features of a poorly differentiated sarcoma, possibly rhabdomyosarcoma. Further investigations revealed a tumour in the lower pole of the right kidney which was subsequently shown to be a malignant rhabdoid tumour. The child was given chemotherapy but re-presented at 10 months of age with hydrocephalus, irritability and spasms leading to death. At autopsy a large tumour was found filling the right lateral and third ventricles; histology showed a primitive neuroectodermal tumour with focal astrocytic differentiation. Residual rhabdoid tumour was restricted to a few para-aortic lymph nodes and focal lymphatic micrometastases in lungs. The association of two embryonal neoplasms of possible similar histogenesis is discussed.     

Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour

Wilms tumour has been reported in association with over 50 different clinical conditions and several abnormal constitutional karyotypes. Conclusive evidence of an increased risk of Wilms tumour exists for only a minority of these conditions, including WT1 associated syndromes, familial Wilms tumour, and certain overgrowth conditions such as Beckwith-Wiedemann syndrome. In many reported conditions the rare co-occurrence of Wilms tumour is probably due to chance. However, for several conditions the available evidence cannot either confirm or exclude an increased risk, usually because of the rarity of the syndrome. In addition, emerging evidence suggests that an increased risk of Wilms tumour occurs only in a subset of individuals for some syndromes. The complex clinical and molecular heterogeneity of disorders associated with Wilms tumour, together with the apparent absence of functional links between most of the known predisposition genes, suggests that abrogation of a variety of pathways can promote Wilms tumorigenesis.     

Inherited endocrinopathies: an update

Inherited endocrinopathies, including multiple endocrine neoplasia type 1 (MEN-1), multiple endocrine neoplasia type 2 syndromes (MEN-2A, MEN-2B, familial medullary thyroid carcinoma), and inherited syndromes with pheochromocytoma (von Hippel–Lindau disease, neurofibromatosis type 1, others), comprise a heterogeneous group of cancer susceptibility syndromes that affect one or more components of the endocrine system. During the past several years, novel findings regarding genotype–phenotype correlation have highlighted the importance of establishing a genetic diagnosis in the treatment of these diseases. Here, we present a case-based review of recent advances in the genetics, diagnosis and management of inherited endocrinopathies.     

Soft tissue tumours in childhood

The spectrum of soft tissue tumours in youg adults is very similar to that in more mature individuals, while those in childhood form a distinct group rarely seen outside the first decade. The majority of these are benign vascular or fibroblastic proliferations; in young children they may be highly cellular and mitotically active, but malignancy should be diagnosed with caution. Congenital soft tissue tumours constitute a special group in which the clinical outcome may be particularly difficult to predict from the histological appearances. This review focuses on those malignant soft tumours which are either peculiar to childhood or which manifest special features in childhood. Some recently recognized benign soft tissue tumours which occur mainly in childhood are also described. The fibromatoses are not discussed. As a guide to the appropriate treatment regime, the main histological distinctions to be drawn are between: 1 tumours of neuroectodermal origin (Ewing's sarcoma and primitive neuroectodermal tumour); 2 other sarcomas; and 3 the fibromatoses and other benign and potentially locally aggressive lesions requiring local excision. Immunohistochemical staining may be of considerable help in achieving the correct diagnosis, but it is vital that a panel of antibodies be applied and the results critically assessed. Cytogenetic analysis is also of growing importance, characteristic karyotypic abnormalities having been demonstrated in Ewing's sarcoma/primitive neuroectodermal tumour, alveolar rhabdomyosarcoma and synovial sarcoma.     

恶性肿瘤患者化疗后感染的临床分析及治疗

目的探讨化疗后恶性肿瘤患者感染因素分析,为临床合理用药提供依据。方法回顾性分析了我院近5年56例化疗后发生感染的肿瘤病人资料。结果恶性肿瘤患者感染的好发部位为呼吸道、消化道、泌尿道、血液等,导致感染病原菌以革兰氏阴性菌为主,占61.5%,感染病原菌依次为绿脓杆菌、克雷伯菌、大肠埃希菌、表皮葡萄球菌、金黄色葡萄球菌及真菌等。结论恶性肿瘤患者化疗感染时,在应用强有力广谱抗生素药物治疗同时,应防止患者合并真菌感染,应用粒细胞集落刺激因子促进白细胞恢复,加强支持治疗。     

The hyper-IgE syndromes

The hyper IgE syndromes (HIES) are rare primary immune deficiencies characterized by elevated serum IgE, rash, and recurrent bacterial infections of the skin and lung. Autosomal dominant HIES, the most common disease in this group, results from STAT3 mutations and has a variety of connective tissue and skeletal abnormalities. The genetic etiologies of the more rare autosomal recessive forms still need delineation. Treatment of these syndromes has relied on prophylactic and therapeutic antimicrobial agents and aggressive skin care. The new and evolving genetic and immunologic understandings of this previously elusive set of diseases should lead to more effective disease-specific therapies.     

Hypermobile Ehlers–Danlos syndrome: A review and a critical appraisal of published genetic research to date

The Ehlers–Danlos syndromes (EDS) are a collection of rare hereditary connective tissue disorders with heterogeneous phenotypes, usually diagnosed following clinical examination and confirmatory genetic testing. Diagnosis of the commonest subtype, hypermobile Ehlers–Danlos Syndrome (hEDS), relies solely on a clinical diagnosis since its molecular aetiology remains unknown. We performed an up-to-date literature search and selected 11 out of 304 publications according to a set of established criteria. Studies reporting variants affecting collagen proteins were found to be hindered by cohort misclassification and subsequent lack of reproducibility of these genetic findings. The role of the described variants affecting Tenascin-X and LZTS1 is yet to be demonstrated in the majority of hEDS cases, while the functional implication of associated signaling pathways and genes requires further elucidation. The available literature on the genetics of hEDS is scant, dispersed and conflicting due to out-dated nosology terminology. Recent literature has suggested the role of several promising candidate mechanisms which may be linked to the underlying molecular aetiology. Knowledge of the molecular genetic basis of hEDS is expected to increase in the near future through the mainstream use of high-throughput sequencing combined with the updated classification of EDS, and the upcoming Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study.     

Juxtacortical malignant schwannoma with heterologous elements

A case of malignant schwannoma with heterologous elements occurring in the periosteum of a long bone is reported. We believe that this is the first time such a tumour has been reported at this site.     

Genetic disorders of collagen.

Osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan syndrome form a group of genetic disorders of connective tissue. These disorders exhibit remarkable clinical heterogeneity which reflects their underlying biochemical and molecular differences. Defects in collagen types I and III have been found in all three syndromes.     

Prognosis in patients with thin malignant melanoma: influence of regression

It has been suggested that patients with thin malignant melanoma displaying evidence of histological regression may have a poor prognosis. In the present study, the case histories of 353 patients with clinical stage I cutaneous malignant melanoma up to 0.7 mm thick were reviewed to determine if either active or past regression in these lesions was a poor prognostic sign. Lesions were reported as displaying evidence of partial regression if either (a) a portion of the melanoma had a heavy lymphocytic infiltrate associated with loss of tumour cells or the presence of degenerating tumour cells, or (b) a portion of the melanoma was replaced by vascular fibrous tissue with or without pigment-containing phagocytes. The incidence of regression in this study (58%) was similar to that reported in another recent large study on thin lesions (53%). Only slightly more regressed than unregressed lesions metastasized (8% versus 5% respectively). A high proportion of first recurrences from these thin lesions developed at sites remote from the primary lesion (lung, bone or in subcutaneous tissues or lymph nodes wide of the line of spread). However, the presence or absence of regression in thin lesions did not appear to influence the site of first recurrence. Cumulative 10-year survival rates for patients whose lesions displayed or did not display evidence of either active or past regression were nearly identical.(ABSTRACT TRUNCATED AT 250 WORDS)     

Familial endocrine tumours: pheochromocytomas and extra-adrenal paragangliomas – an update

Pheochromocytomas (PCC) and paragangliomas (PGL) are tumours occurring in the adrenal medulla and in extra-adrenal paraganglia, respectively. They have long been associated with familial occurrence and several syndromes had been described in which PCC formed an important component, including multiple endocrine neoplasia type 2, von Hippel-Lindau disease and neurofibromatosis type 1. Since the beginning of this millennium, both by the elucidation of specific genes, such as the various succinate dehydrogenase genes, as well as by generic molecular biology approaches, such as The Cancer Genome Atlas (TCGA) initiative, it was shown that the frequency of germline mutations in candidate genes for PCC and PGL has increased to 35–40%. In addition, somatic mutations have been shown to be much more frequent than previously thought, such that now 60–65% of these tumours harbour either a germline or a somatic mutation. This review gives an overview of the various syndromes and the genes involved, concluding with recommendations for genetic testing in the current era of genome wide analysis.     

Solving the genetic aetiology of hereditary gastrointestinal tumour syndromes– a collaborative multicentre endeavour within the project Solve-RD

BackgroundPatients and families with suspected, but genetically unexplained (unsolved) genetic tumour risk syndromes lack appropriate treatment and prevention, leading to preventable morbidity and mortality. To tackle this problem, patients from the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) are analysed in the European Commission's research project “Solving the unsolved rare diseases” (Solve-RD). The aim is to uncover known and novel cancer predisposing genes by reanalysing available whole-exome sequencing (WES) data of large cohorts in a combined manner, and applying a multidimensional omics approach.ApproachAround 500 genetically unsolved cases with suspected hereditary gastrointestinal tumour syndromes (polyposis, early-onset/familial colorectal cancer and gastric cancer) from multiple European centres are aimed to be included. Currently, clinical and germline WES data from 294 cases have been analysed. In addition, an extensive molecular profiling of gastrointestinal tumours from these patients is planned and deep learning techniques will be applied. The ambitious, multidisciplinary project is accompanied by a number of methodical, technical, and logistic challenges, which require the development and implementation of new analysis tools, the standardisation of bioinformatics pipelines, and strategies to exchange data and knowledge.Resultsand Outlook. The first re-analysis of 229 known and proposed cancer predisposition genes allowed solving 2–3% of previously unsolved GENTURIS cases. The integration of expert knowledge and new technologies will help to identify the genetic basis of additional unsolved cases within the ongoing project. The ERN GENTURIS approach might serve as a model for other genomic initiatives.