Surveillance in von Hippel-Lindau disease (vHL)

Poulsen MLM, Budtz-Jørgensen E, Bisgaard ML. Surveillance in von Hippel-Lindau disease (vHL).
von Hippel-Lindau disease (vHL) is a hereditary multisystem cancer syndrome requiring lifelong prophylactic surveillance. Current surveillance recommendations rely on best medical judgement and no evidence of effect exists. We aimed to evaluate the capability of surveillance in manifestation detection, before these turn symptomatic, in order to prevent disabling or even fatal outcomes. We focus on surveillance of central nervous system (CNS) hemangioblastomas, retinal hemangiomas and renal cell carcinoma (RCC) as these have the most severe consequences. On the basis of full medical records from 54 living vHL -mutation carriers, risks of intercurrent manifestations in-between surveillance examinations were determined and clinical consequences of surveillance findings evaluated. Current recommendations of annual ophthalmic and abdominal examinations corresponded to acceptably low intercurrent manifestation risks (1.7% and 1.2%, respectively), whereas recommendations of biennial CNS imaging corresponded to a risk of 7.2%. Annual CNS examinations, however, significantly reduces this risk to 2.7%. Furthermore, most CNS manifestations found due to surveillance (71%, 106 of 150) had clinical consequence for the patient. Also, pre-symptomatic surveillance increased cumulative incidence of clinical vHL diagnosis from 46% to 72% and from 89% to 94% by age 30 and 50 years, respectively. The present results promote optimization of surveillance, expectantly improving clinical vHL outcomes.     

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.     

Metastatic renal cell carcinoma to hemangioblastoma in von Hippel-Lindau disease

A case of metastatic renal cell carcinoma (RCC) to a capillary hemangioblastoma (HAB) of the central nervous system in a 52-year-old woman with von Hippel-Lindau (vHL) syndrome is described. We review the literature on metastatic RCC to HAB, summarize the histologic and immunohistochemical features that can distinguish between the 2 tumors, and comment on the significance of such a finding in terms of the clinical diagnosis of vHL. We found the expression of CAM 5.2, RCC antigen, and CD10 to be strong in RCC and absent in HAB and, conversely, staining with Leu-7, neural cell adhesion molecule, and inhibin-alpha was present in HAB but weak or absent in RCC. These antibodies can be used to differentiate these entities, provided one is astute in recognizing the possibility of their coexistence.     

Risk of new tumors in von Hippel–Lindau patients depends on age and genotype

PurposeThe von Hippel–Lindau (vHL) phenotype is variable, which complicates genetic counseling and surveillance. We describe how the rate of new tumor development varies through the lifetimes of vHL patients and how it is influenced by age and genotype.MethodsIn a national cohort study, we included 52 VHL mutation carriers who were retrospectively followed for a total of 799 person-years. From birth to current age, 581 manifestations were diagnosed during 2,583 examinations in the study subjects. Manifestation rates were analyzed using Poisson regression and compared in groups of different ages, tumor sites, and genotypes.ResultsThe rate of new tumor development varied significantly with age and was highest at 30–34 years (0.4 new tumors/year). Tumor location further influenced the rate. The risk of retinal tumors was highest in subjects during the teenage years but was highest for cerebellar tumors in subjects during their 30s. Truncating VHL mutation carriers had a significantly higher manifestation rate compared with missense mutation carriers (hazard ratio = 1.85, 95% confidence interval: 1.06–3.24, P value = 0.031).ConclusionThe rate of new manifestation development is not constant throughout the life span of vHL patients; instead, it varies significantly with age and genotype and depends on anatomical location. Retinal surveillance is crucial during the teenage years, whereas cerebellar surveillance is especially important in adulthood.     

Morphologie, DNA-Zytophotometrie und Prognose gastrointestinaler neuroendokriner Tumoren (Karzinoide)

A total of 123 manifestations (97 primary tumours and 26 metastases) of neuroendocrine tumours of the gastrointestinal tract observed in 95 patients was investigated for the prognostic value of clinical, histological and DNA cytophotometric parameters. Metastases almost exclusively occurred among ileal carcinoids, which also were responsible for all 14 cases of lethal outcome observed during the follow-up period of mean 42 months. Aneuploid DNA values could be determined significantly more frequently among ileal than in non-ileal carcinoids and showed - upon analysis of the total group of gastrointestinal neuroendocrine tumours - a significant correlation to lethal course of disease. In addition, among 18 cases with primary and secondary carcinoid manifestations available for DNA cytophotometry, an association between the DNA content of metastatic neuroendocrine tumours and prognosis came to light. When applied to the group of ileal neoplasms, however, the parameter DNA content did not allow a better prognostic assessment.     

Magnetic Resonance Imaging in the Evaluation of Central Nervous System Manifestations in Systemic Lupus Erythematosus

Central nervous system (CNS) manifestations are often observed in systemic lupus erythematosus (SLE) patients during the course of their disease. The prevalence of CNS manifestations ranges between 17 and 75%, reflecting different methods of patient selection and assessment, varying levels of assessor expertise, and lack of a consensus for diagnosing active and chronic neuropsychiatric (NP) manifestations. Postulated pathogenic mechanisms of peripheral and CNS events include vasculopathy, autoantibody effects, and systemic inflammation. Diagnosis is often difficult because of the lack of standardized diagnostic techniques. Magnetic resonance imaging (MRI) is considered the gold standard for the evaluation of CNS manifestations in SLE patients in clinical practice. MRI findings are diverse, and atrophy and hyperintense white matter lesions often correlate poorly with clinical manifestations, occurring also in patients without marked CNS signs and symptoms. We will describe MRI findings in SLE patients and discuss the usefulness of different MRI techniques in evaluating acute and chronic CNS manifestations.     

del(3p)(p13p21) in renal cell adenoma and del(4p)(p14) in bilateral renal cell carcinoma in two unrelated patients with von Hippel-Lindau disease

Karyotype analyses of renal cell adenoma in one patient and bilateral renal cell carcinomas (RCC) in another unrelated patient have been performed. Both patients belonged to families with von Hippel-Lindau disease (vHL). In the adenoma, we found a clonal del(3)(p13p21) and a small clone of two cells with an additional del(14)(q13). This result indicates that the same region that is often deleted in RCC may also be deleted in a renal cortical adenoma. This finding may facilitate the localization of a tentative renal cell adenoma/carcinoma tumor suppressor locus. In the tumors from the patient with bilateral carcinomas we found a clonal del(4)(p14) on one side and on the other a del(4)(p14) together with del(14)(q13). In this case, there was no detectable 3p defect in the tumors. This result raises the question whether an alternative/additional locus on chromosome 4p may be involved in the RCC/vHL syndrome. Constitutional karyotypes were in both cases normal.     

Clinical Characteristics of Renal Cell Carcinoma in Korean Patients with von Hippel-Lindau Disease Compared to Sporadic Bilateral or Multifocal Renal Cell Carcinoma

This study was done to analyze the clinical characteristics of renal cell carcinoma (RCC) in Korean patients with von Hippel-Lindau (VHL) disease. Between January 1996 and July 2008, 1,514 patients were diagnosed with RCC and 24 patients were diagnosed with VHL disease at our institute. We analyzed the clinical characteristics of the 24 patients diagnosed with VHL. The mean age of patients with VHL was 39.2±12.6 yr; the mean age of patients with both VHL and RCC was 42.5±10.3 yr. Among the 24 patients with VHL, 7 patients had retinal angiomas, 11 had RCC, 16 had renal lesions, 18 had pancreatic lesions and 21 had cerebellar hemangioblastomas. There was no significant difference between survival rates of patients with VHL alone and those with VHL and RCC. However, cancer-specific survival rates were significantly different between patients with both VHL and RCC and patients with sporadic bilateral or multifocal RCC. In our Korean study, the incidence of RCC in patients with VHL disease is 45.8% and the incidence of VHL disease in patients with RCC is 0.73%. Due to the low overall incidence of VHL in Korea, extended multi-institutional studies are needed to establish the true characteristics of VHL disease.     

Expanding on the phenotypic spectrum of Woodhouse-Sakati syndrome due to founder pathogenic variant in DCAF17: Report of 58 additional patients from Qatar and literature review

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive neuroendocrine and ectodermal disorder caused by variants in the DCAF17 gene. In Qatar, the c.436delC variant has been reported as a possible founder pathogenic variant with striking phenotypic heterogeneity. In this retrospective study, we report on the clinical and molecular characteristics of additional 58 additional Qatari patients with WSS and compare them to international counterparts' findings. A total of 58 patients with WSS from 32 consanguineous families were identified. Ectodermal and endocrine (primary hypogonadism) manifestations were the most common presentations (100%), followed by diabetes mellitus (46%) and hypothyroidism (36%). Neurological manifestations were overlapping among patients with intellectual disability (ID) being the most common (75%), followed by sensorineural hearing loss (43%) and both ID and aggressive behavior (10%). Distinctive facial features were noted in all patients and extrapyramidal manifestations were uncommon (8.6%). This study is the largest to date on Qatari patients with WSS and highlights the high incidence and clinical heterogeneity of WSS in Qatar due to a founder variant c.436delC in the DCAF17 gene. Early suspicion of WSS among Qatari patients with hypogonadism and ID, even in the absence of other manifestations, would shorten the diagnostic odyssey, guide early and appropriate management, and avoid potential complications.     

Identifying challenges in neurofibromatosis: a modified Delphi procedure

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are rare conditions with pronounced variability of clinical expression. We aimed to reach consensus on the most important manifestations meriting the development of drug trials. The five-staged modified Delphi procedure consisted of two questionnaires and a consensus meeting for 40 NF experts, a survey for 63 patient representatives, and a final workshop. In the questionnaires, manifestations were scored on multiple items on a 4-point Likert scale. The highest average scores for NF experts deciding the ‘need for new treatment’ were for malignant peripheral nerve sheath tumour (MPNST) (4,0) and high grade glioma (HGG) (3,9) for NF1; meningioma (3,9) for NF2 and pain (3,9) for SWN. The patient representatives assigned high scores to all manifestations, with plexiform neurofibroma being highest in NF1 (4,0), vestibular schwannoma in NF2 (4,0), and pain in SWN (3,9). Twelve experts participated in the consensus meeting and prioritised manifestations. MPNST was ranked the highest for NF1, followed by benign peripheral nerve sheath tumours. Tumour manifestations received highest ranking in NF2, and pain was the most prominent problem for SWN. Patient representative ratings for NF1 were similar to the experts’ opinions, except that they ranked HGG as the most important manifestation. For NF2 and SWN, the patient representatives agreed with the experts. We conclude that NF experts and patient representatives consent to prioritise development of drug trials for MPNST, benign peripheral nerve sheath tumours, cutaneous manifestations and HGG for NF1; tumours for NF2; and pain for SWN.Subject terms: Neurodevelopmental disorders, Adaptive clinical trial     

A systematic review assessing the existence of pneumothorax-only variants of FLCN. Implications for lifelong surveillance of renal tumours

Individuals with Birt–Hogg–Dubé syndrome (BHDS) may develop fibrofolliculomas, pneumothorax and/or renal cell carcinoma (RCC). Currently, all patients with pathogenic FLCN variants are recommended to have renal surveillance. It has however been suggested that some FLCN variants only cause pneumothorax, which would make surveillance unnecessary in certain cases. This review assesses this possibility. We provide an up-to-date analysis of clinical and genetic features of BHDS. The PUBMED database was systematically searched to find all articles describing patients with pathogenic FLCN variants. The relevant clinical and genetic features of these patients were recorded and analysed. The prevalence of pneumothorax, pulmonary cysts, RCC and characteristic skin lesions in BHDS were 50.9% (n = 1038), 91.9% (n = 720), 22.5% (n = 929) and 47.9% (n = 989), respectively. There was a higher prevalence of pneumothoraces (p < 0.0001) but lower prevalence of dermatological findings (p < 0.0001) in patients from East Asia compared to North America or Europe. Of the 194 pathogenic FLCN variants, 76 could be defined as ‘pneumothorax-only’. Pneumothorax only pathogenic variants (POPVs) were distributed throughout the gene, and there were no statistical differences in variant type. The majority of POPVs (65/76) affected no more than three individuals. Individuals with ‘POPVs’ also tended to be younger (45 vs. 47 years, p < 0.05). Many apparent POPVs in the literature could result from variable expressivity, age-related penetrance and other confounding factors. We therefore recommend that all individuals found to carry a pathogenic FLCN variant be enroled in lifelong surveillance for RCC.Subject terms: Clinical genetics, Respiratory tract diseases     

中国人一个von Hippel-Lindau病的大家系调查及基因突变研究

目的 探讨中国人一个von Hippel-Lindau(VHL)病家系的临床特点及基因突变研究的临床意义。方法 调查一个von Hippel—Lindau病大家系，制定该家系发病的树状图；抽取27位家族成员外周血，采用聚合酶链反应和扩增产物直接测序进行基因检测；通过病史和影像学检查，获得该病的多脏器肿瘤发生情况。结果 该家族4代47人中18人患von Hippel-Lindau病，其中中枢神经系统成血管细胞瘤5例，肾癌合并中枢神经系统成血管细胞瘤3例，肾癌合并视网膜血管瘤3例，肾癌合并胰腺多发性囊肿1例，肾癌合并视网膜血管瘤及胰腺多发性囊肿2例，肾癌合并中枢神经系统成血管细胞瘤及胰腺多发性囊肿1例，肾脏多发性囊肿合并胰腺多发性囊肿1例和胰腺多发性囊肿2例。本组中，肾癌、中枢神经系统成血管细胞瘤、视网膜血管瘤和胰腺多发性囊肿的发生率分别为56％、50％、28％和39％。基因检测发现VHL基因第1外显子上第446位核苷酸A→G突变，该突变导致第78位编码氨基酸由天冬酰胺转变为丝氨酸。检测的27人中，15人呈现VHL基因突变，其中9例患病者、4例致病基因携带者及2例经影象学检查外科手术证实的无症状患者。其余12人无基因突变，同时无相应临床征象。结论 该家系属于von Hippel—Lindau病I型，肾癌发生率高而视网膜血管瘤发生率低是其主要的临床特点。基因检测在早期发现无症状患者和致病基因携带者及对该病家族成员进行临床监测方面起着重要作用，并在遗传生殖角度阻断该疾病的遗传有重要意义。     

Rare embryonal and sarcomatous central nervous system tumours: State-of-the art and future directions

The introduction of molecular methods into the diagnostics of central nervous system (CNS) tumours and the subsequent deciphering of their molecular heterogeneity has resulted in a significant impact on paediatric neurooncology. Particularly in the field of rare embryonal and sarcomatous CNS tumours, novel tumour types have been delineated and introduced in the recent 5th edition of the WHO classification of CNS tumours. The rarity and novelty of these tumour types result in diagnostic and therapeutic challenges. Apart from distinct histopathological and molecular features, these tumour types exhibit characteristic clinical properties and require different therapeutic approaches for optimal patient management. However, based on the limited availability of clinical data, current therapeutic recommendations have to be based on data from small, predominantly retrospective patient cohorts. Within this article, we provide guidance for diagnostic work-up and clinical management of rare CNS embryonal tumours (‘embryonal tumour with multi-layered rosettes’, ETMR; ‘CNS neuroblastoma, FOXR2-activated’, CNS NB-FOXR2; ‘CNS tumour with BCOR-ITD, CNS BCOR-ITD) and rare CNS sarcomatous tumours (‘primary intracranial sarcoma, DICER1-mutant’, CNS DICER1; ‘CIC-rearranged sarcoma’, CNS CIC). By emphasizing the significant consequences on patient management in paediatric CNS tumours, we want to encourage wide implementation of comprehensive molecular diagnostics and stress the importance for joint international efforts to further collect and study these rare tumour types.     

中枢神经系统血管母细胞瘤MRI特点分析

目的 进一步提高对中枢神经系统血管母细胞瘤MRI特点的认识。方法 搜集经手术病理证实的中枢神经系统血管母细胞瘤21例，对其MRI表现进行回顾性分析。结果 血管母细胞瘤常见于后颅窝，发生于椎管内者少见。本组21例23个病灶，大囊小结节型9例，实质型10例，单纯囊型2例。血管母细胞瘤典型表现为大囊、小结节且结节显著异常强化。实质型MRI特征性不强，术前误诊率高达70％，尤其脊髓内实质型，术前MRI正确诊断率仅为20％。结论 MRI是诊断血管母细胞瘤的有效检查方法，MRI增强对于血管母细胞瘤的正确诊断和分型尤为重要。     

Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity

Inherited renal cell carcinoma (RCC) is associated with multiple familial cancer syndromes but most individuals with features of non‐syndromic inherited RCC do not harbor variants in the most commonly tested renal cancer predisposition genes (CPGs). We investigated whether undiagnosed cases might harbor mutations in CPGs that are not routinely tested for by testing 118 individuals with features suggestive of inherited RCC (family history of RCC, two or more primary RCC aged <60 years, or early onset RCC ≤46 years) for the presence of pathogenic variants in a large panel of CPGs. All individuals had been prescreened for pathogenic variants in the major RCC genes. We detected pathogenic or likely pathogenic (P/LP) variants of potential clinical relevance in 16.1% (19/118) of individuals, including P/LP variants in BRIP1 (n = 4), CHEK2 (n = 3), MITF (n = 1), and BRCA1 (n = 1). Though the power to detect rare variants was limited by sample size the frequency of truncating variants in BRIP1, 4/118, was significantly higher than in controls (P = 5.92E‐03). These findings suggest that the application of genetic testing for larger inherited cancer gene panels in patients with indicators of a potential inherited RCC can increase the diagnostic yield for P/LP variants. However, the clinical utility of such a diagnostic strategy requires validation and further evaluation and in particular, confirmation of rarer RCC genotype‐phenotype associations is required.     

Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location

von Hippel Lindau disease (VHL) is an autosomal dominant familial cancer syndrome linked to alteration of the VHL tumor suppressor gene. Affected patients are predisposed to develop pheochromocytomas and cystic and solid tumors of the kidney, CNS, pancreas, retina, and epididymis. However, organ involvement varies considerably among families and has been shown to correlate with the underlying germline alteration. Clinically, we observed a paradoxically lower prevalence of renal cell carcinoma (RCC) in patients with complete germline deletion of VHL. To determine if a relationship existed between the type of VHL deletion and disease, we retrospectively evaluated 123 patients from 55 families with large germline VHL deletions, including 42 intragenic partial deletions and 13 complete VHL deletions, by history and radiographic imaging. Each individual and family was scored for cystic or solid involvement of CNS, pancreas, and kidney, and for pheochromocytoma. Germline deletions were mapped using a combination of fluorescent in situ hybridization (FISH) and quantitative Southern and Southern blot analysis. An age-adjusted comparison demonstrated a higher prevalence of RCC in patients with partial germline VHL deletions relative to complete deletions (48.9 vs. 22.6%, p=0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p=0.22), pancreas (p=0.72), or pheochromocytoma (p=0.34). Deletion mapping revealed that development of RCC had an even greater correlation with retention of HSPC300 (C3orf10), located within the 30-kb region of chromosome 3p, immediately telomeric to VHL (52.3 vs. 18.9%, p <0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC. Careful correlation of genotypic data with objective phenotypic measures will provide further insight into the mechanisms of tumor formation.     

The Cohen syndrome: does mottled retina separate a Finnish and a Jewish type?

A new familial cases of the Cohen syndrome in two brothers of one-half second-cousin parents is reported. Typical clinical manifestations of the syndrome; i.e., mental deficiency, hypotonia, characteristic facial appearance, long, narrow hands and feet with elongated fingers, and mottled retinae were present in both patients. Both patients also had leukopenia. Clinical manifestations of the Cohen syndrome in patients are highly variable, and mottled retina has been observed in 22 of 87 patients (25%). However, an association of mottled retina in patients with the Cohen syndrome is likely to be related to the families and ethnic groups. Among 19 familial cases, mottled retina was observed in all affected sibs from five families, but in 13 families none of the affected sibs had the mottled retina. All Finnish patients had the mottled retina, but this was noted in only one of 39 Jewish patients. Based on these data, we hypothesize that two alleles at the gene locus for the Cohen syndrome exhibit different clinical manifestations: one is a Finnish type with mottled retina, and the other is a Jewish type without retinal anomalies.     

Population‐based survey of cancer risks in chromosome 3 translocation carriers

Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be associated with germline mutations in a number of genes. Twelve different constitutional translocations involving chromosome 3 have also been described in association with inherited RCC. In some families the lifetime risk of RCC in chromosome 3 translocation carriers has been estimated to be more than 80%; however the cancer risks in patients with chromosome 3 translocations not ascertained because of a family history of RCC are not well defined. We report a retrospective population‐based study using Danish national cytogenetic and cancer registries to clarify tumor risks associated with constitutional translocations involving chromosome 3. We identified 222 (105 females, 117 males) individuals with a constitutional chromosome 3 translocation and compared their cancer risks to those of the Danish population. None of the chromosome 3 translocation carriers had developed RCC at the time of study (female 95% CIs 0.000–0.042, male 95% CIs 0.000–0.038) (P = 1.0 and P = 0.498 for females and males compared to Danish population). Fourteen translocation carriers had developed cancer but there was no evidence of an excess of early onset disease and lifetime cancer risks in chromosome 3 translocation carriers were similar that in the Danish population. There was no association between cancer risk and location of the chromosome 3 breakpoint (HR = 1.322, P = 0.673). These findings suggest that, in the absence of a family history of RCC or evidence of disruption of a specific tumor suppressor gene, chromosome 3 translocations carriers are not at high risk of developing RCC. © 2009 Wiley‐Liss, Inc.     

Alu‐Alu recombination underlies the vast majority of large VHL germline deletions: Molecular characterization and genotype–phenotype correlations in VHL patients

Von Hippel‐Lindau disease (VHL) is an autosomal dominant cancer syndrome. Affected individuals are predisposed to multiple tumors, primarily of the central nervous system (CNS), eyes, adrenals, and kidneys. The VHL tumor suppressor gene on chromosome 3p26–25 is partially or completely deleted in 20 to 30% of families with VHL. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families. In 33 of the index patients, the breakpoints were precisely characterized by DNA sequencing. Of the 66 breakpoints, 90% were located in Alu elements, revealing Alu‐mediated recombination as the major mechanism for large germline deletions of the VHL gene, which lies in a region of high Alu density. Interestingly, an AluYa5 element in VHL intron 2, the evolutionarily youngest Alu element and the only such element in the entire region, was found to be the most recombinogenic, involved in 7 out of the 33 deletions. In comparison to VHL patients in general, the 54 index cases and their affected relatives showed a higher occurrence of renal cell carcinomas (RCC) and of CNS hemangioblastomas. We not only noted the association of RCC with retention of the HSPC300 gene, but also observed a significant correlation between retention of HSPC300 and the development of retinal angiomas (AR). This study reveals that germline VHL deletions provide a particularly rich source for the study of Alu‐mediated unequal crossover events, and provides evidence for a protective role of the loss of the actin‐regulator gene HSPC300 for the development of both RCC and AR. Hum Mutat 30, 1–11, 2009. © 2009 Wiley‐Liss, Inc.     

Tumors of the thymus

Tumours of the thymus include heterogenic group of benign and malignant organ-specific (thymomas and carcinoma) and organ-nonspecific (neuroendocrine, germinogenic tumours, lymphomas and others) neoplasms. Histologic classifications are now the most useful for the correlation with prognosis and clinical manifestations. It is obligatory to do verification of the progression stage.