Abdominal neoplastic manifestations of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome, with a wide clinicopathologic spectrum. It is defined by characteristic central nervous system, cutaneous and osseous manifestations, and by mutations in the NF1 gene, which is involved in proliferation via p21, RAS, and MAP kinase pathways. Up to 25% of NF1 patients develop intra-abdominal neoplastic manifestations including neurogenic (commonly plexiform neurofibromas and malignant peripheral nerve sheath tumors), interstitial cells of Cajal (hyperplasia, gastrointestinal stromal tumors), neuroendocrine, and embryonal tumors (rhabdomyosarcoma). Nonspecific symptoms, multifocal disease, or coexistence of 2 or more tumor types make patients challenging to diagnose and manage. Screening for intra-abdominal tumors in NF1 patients remains controversial, and currently no guidelines are established. Management decisions are complex and often informed by single-center experiences or case studies in the literature, though the field is rapidly evolving. Thus, NF1 patients should be followed in specialist centers familiar with their wide spectrum of pathology and with multidisciplinary care including specialized pathology and radiology. This review will (1) provide a contemporaneous synthesis of the literature and our multi-institutional clinical experiences with intra-abdominal neoplasms in NF1 patients, (2) present a classification framework for this heterogeneous group of disorders, and (3) outline approaches to screening, surveillance, diagnosis, and management.

Succinate Dehydrogenase–Deficient Renal Cell Carcinoma: A Short Review

Succinate dehydrogenase (SDH) is a mitochondrial enzyme complex composed of 4 protein subunits (SDHA, SDHB, SDHC, and SDHD). Germ line mutations of the genes encoding these SDH subunits result in hereditary syndromes harboring pheochromocytomas/paragangliomas, gastrointestinal stromal tumors, renal cell carcinomas, and pituitary adenomas. SDH-deficient renal cell carcinomas are rare, with a mean age of 38 to 40 years. Histologically, these tumors show a characteristic appearance that includes a solid, nested, or tubular architecture with variable cysts. Cells are typically cuboidal, have indistinct cell borders and eosinophilic cytoplasm, and show flocculent intracytoplasmic inclusions. Loss of immunohistochemical staining for SDHB is the hallmark of these tumors. Although most SDH-deficient renal cell carcinomas are clinically indolent, some tumors may behave aggressively, particularly those with a high nuclear grade, tumor necrosis, or sarcomatoid differentiation. Accurate classification of these tumors is important for clinical follow-up, screening, and genetic evaluation of the patients and other family members for this hereditary tumor syndrome.

Exploring the role of defective fibronectin matrix assembly in the VHL-associated CNS hemangioblastoma

Background:Central nervous system (CNS) hemangioblastoma (HB) is the most common tumor in the von Hippel Lindau (VHL) disorder, the hereditary tumor syndrome caused by the biallelic mutations of theVHLgene. The disrupted VHL and Elongin protein interaction on hypoxia-inducible factor-1α (HIF-1α) induces a set of hypoxia-inducible genes, resulting in an unchecked endothelial cell proliferation that then leads to hemangioblastoma formation. However, recent studies have shown that disruptive germline mutations ofVHLneed not result in hemangioblastoma, though it can cause other manifestations of the VHL syndrome. Similarly, sporadic hemangioblastoma can occur rarely without a somatic biallelicVHLmutation. The VHL protein was earlier found to be associated with the deposition of matrix fibronectin (FN) protein in the renal extracellular matrix.Methods:The present study was designed to investigate the deposition of the matrix FN protein in VHL-associated hemangioblastoma.Results:Seven HB tumor samples from the VHL syndrome had lower expressions of tissue FN compared to the control cerebellum samples or the control blood vessel sample. On comparing the VHL and FN protein expressions in a timed endothelial tube assay, the VHL protein expression was absent during the initial phase of tube formation but started expressing after 6 h. The levels of matrix form of FN gradually increased along with the VHL expression during the maturation of tube formation. Tube formation was found to be enhanced with extraneously added soluble FN and inhibited by matrix FN. Similarly, tube formation was inhibited by a modified tripeptide (RGD) inhibitor of integrin (-αVβ3), namely, Cyclo-Ala-Arg-Gly-Asp-3-aminomethylbenzoyl.Conclusions:Our study implicates that the extracellular deposition and matrix formation of FN is important for vascular endothelial proliferation, and that its absence has roles in the development of hemangioblastoma in the VHL syndrome.

A comprehensive review on MEN2B

MEN2B is a very rare autosomal dominant hereditary tumor syndrome associated with medullary thyroid carcinoma (MTC) in 100% cases, pheochromocytoma in 50% cases and multiple extra-endocrine features, many of which can be quite disabling. Only few data are available in the literature. The aim of this review is to try to give further insights into the natural history of the disease and to point out the missing evidence that would help clinicians optimize the management of such patients. MEN2B is mainly characterized by the early occurrence of MTC, which led the American Thyroid Association to recommend preventive thyroidectomy before the age of 1 year. However, as the majority of mutations are de novo, improved knowledge of the nonendocrine signs would help to lower the age of diagnosis and improve long-term outcomes. Future large-scale studies will be aimed at characterizing more in detail the main characteristics and outcomes of MEN2B.

Germline VHL gene mutations in Hungarian families with von Hippel–Lindau disease and patients with apparently sporadic unilateral pheochromocytomas

ObjectiveVon Hippel–Lindau (VHL) disease is a hereditary tumor syndrome caused by mutations or deletions of theVHLtumor-suppressor gene. GermlineVHLgene alterations may be also present in patients with apparently sporadic pheochromocytoma (ASP), although a wide variation in mutation frequencies has been reported in different patient cohorts.DesignHerein, we report the analysis of theVHLgene in Hungarian families with VHL disease and in those with ASP.MethodsSeven families (35 members) with VHL disease and 37 unrelated patients with unilateral ASP were analyzed. Patients were clinically evaluated and theVHLgene was analyzed using direct sequencing, multiplex ligation-dependent probe amplification, and real-time PCR with SYBR Green chemistry.ResultsDisease-causing genetic abnormalities were identified in each of the seven VHL families and in 3 out of the 37 patients with ASP (one nonsense and six missense mutations, two large gene deletions and one novel 2 bp deletion). Large gene deletions and other genetic alterations resulting in truncated VHL protein were found only in families with VHL type 1, whereas missense mutations were associated mainly, although not exclusively, with VHL type 2B and type 2C.ConclusionsThe spectrum ofVHLgene abnormalities in the Hungarian population is similar to that observed in Western, Japanese, or Chinese VHL kindreds. The presence ofVHLgene mutations in 3 out of the 37 patients with ASP suggests that genetic testing is useful not only in patients with VHL disease but also in those with ASP.