Evidence for aldosterone-dependent growth of renal cell carcinoma.

The aim if this study was to investigate the hypothesis that K-RAS 4A is upregulated in a mineralocorticoid-dependent manner in renal cell carcinoma and that this supports the proliferation and survival of some renal cancers. Expression of the K-RAS in renal tumour tissues and cell lines was examined by real-time PCR and Western blot and mineralocorticoid receptor, and its gatekeeper enzyme 11ß-hydroxysteroid dehydrogenase-2 was examined by immunocytochemistry on a tissue microarray of 27 cases of renal cell carcinoma. Renal cancer cells lines 04A018 (RCC4 plus VHL) and 04A019 (RCC4 plus vector alone) were examined for the expression of K-RAS4A and for the effect on K-RAS expression of spironolactone blockade of the mineralocorticoid receptor. K-RAS4A was suppressed by siRNA, and the effect on cell survival, proliferation and activation of the Akt and Raf signalling pathways was investigated in vitro. K-RAS4A was expressed in RCC tissue and in the renal cancer cell lines but K-RAS was downregulated by spironolactone and upregulated by aldosterone. Spironolactone treatment and K-RAS suppression both led to a reduction in cell number in vitro. Both Akt and Raf pathways showed activation which was dependent on K-RAS expression. K-RAS expression in renal cell carcinoma is at least partially induced by aldosterone. Aldosterone supports the survival and proliferation of RCC cells by upregulation of K-RAS acting through the Akt and Raf pathways.

Type and maturational status of dendritic cells in cutaneous B cell lymphoproliferative disorders.

AIMS: B cell cutaneous lymphoid hyperplasia (B-CLH) and cutaneous mucosa-associated lymphoid tissue (MALT) lymphoma represent opposite poles of the same disease spectrum. We explored the hypothesis that dendritic cells (DCs) are central in the generation and regulation of such lesions. METHODS AND RESULTS: Immunohistochemistry was used to identify Langerhan cells (LCs), dermal DCs (DDCs) and plasmacytoid DCs (PDCs), as well as mature and alternatively activated DCs, in B-CLH (n = 14) and cutaneous MALT lymphoma (n = 18). PDCs were most numerous in both types of lesion, but there were significantly more PDCs and DDCs and greater numbers of mature DCs in B-CLH. Nevertheless, DCs were still present in cutaneous MALT lymphoma and there were also proportionately more alternatively activated cells. CONCLUSION: Mature DDCs are prime activators of naive T cells and our results suggest that they are likely to be largely responsible for driving the initial proliferation in B-CLH. The results also suggest that PDCs play a central role, and we hypothesize that they dictate the magnitude, duration and direction of the response. In cutaneous MALT lymphoma PDCs are the dominant DC subtype, and may act by damping down the antitumour host immune response, as well as directly stimulating the growth and differentiation of the neoplastic lymphocytes.

Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1.

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer.

C-MYC translocation in t(14;18) positive follicular lymphoma at presentation: An adverse prognostic indicator?

Follicular lymphoma (FL) is a common subtype of low grade B-cell non-Hodgkin lymphoma (NHL). Although this form of lymphoma often pursues an indolent course, in some cases it may behave in a more aggressive manner. Clinical and histological parameters have been shown to correlate with an adverse prognosis but a number of cytogenetic abnormalities may also be associated with aggressive disease. Although, the t(14;18) in itself does not affect outcome in cases of FL, secondary abnormalities that occur in a complex polyploid karyotype may identify cases with a poor prognosis. It is unusual to find both t(14;18) and C-MYC translocation in the same tumour; those cases in which it has been described include examples of high-grade B-cell NHL (either de novo or transformed FL) or B-cell acute lymphoblastic lymphoma. In this report, three cases of FL are described in which both t(14;18) and a C-MYC translocation were identified at presentation. We also summarize four further cases from the literature. This is a small series but one which raises the possibility that the presence of a C-MYC translocations at presentation may identify a particularly aggressive subtype of FL. Further studies are required to investigate the true incidence of this aberration, the impact on C-MYC regulation, clinical course and response to treatment.

A simple and rapid approach to the problem of tissue contamination and patient identity in histopathologic specimens.

Individual pathologists deal with thousands of diagnostic biopsy and excision specimens annually. At each stage, procedures are in place to limit the possibility of human error, which could result in specimen transposition or contamination. One specimen contaminating another is usually easily identified and rarely causes diagnostic difficulty; however, when it does, the consequences can be very serious. We discuss 5 cases in which concerns over specimen identity and tissue contamination arose and the methodology by which we resolved those concerns. Polymerase chain reaction analysis of each case was carried out using a panel of 12 polymorphic microsatellite markers, specific for chromosomes 13, 18, and 21. These markers are routinely used in the molecular genetics diagnostic laboratory for rapid trisomy screening. In each case, the question of error was satisfactorily resolved. Using this approach, we prevented the real possibility of patients undergoing second invasive procedures. We suggest that this or a similar methodology become a routine part of pathology practice.

Lesions resembling Langerhans cell histiocytosis in association with other lymphoproliferative disorders: a reactive or neoplastic phenomenon?

Langerhans cell histiocytosis (LCH) has been described in association with a variety of neoplasms preceding, after, or synchronous with the other tumor. In some cases, a neoplasm may arise as a complication of therapy for LCH, and in others, the association may be coincidental. Synchronous occurrence has been reported most commonly in association with malignant lymphoma in which discrete proliferations of Langerhans cells (LCs) histologically indistinguishable from LCH are seen. In most cases, these LCs are closely related to or intermingling with the primary pathology. The nature of LCs in this context remains elusive with debate as to whether they represent a true clonal neoplasm or an exaggerated reactive phenomenon. The lack of evidence for LCH progression or disease elsewhere strongly supports the latter. We have encountered 5 examples of LCH-like proliferations occurring in the context of other lymphoproliferative disorders. These include 2 cases of mycosis fungoides and 1 of cutaneous B-cell pseudolymphoma, associations that to our knowledge have not been described before. Two patients were female, and the clonality of the LC proliferation was assessed using laser capture microdissection and the human androgen receptor. The results showed that the LCs forming discrete nodules in a case of cutaneous B-cell pseudolymphoma and a case of Hodgkin's lymphoma were polyclonal. This suggests that, at least in a proportion of cases, the aggregates of LCs occasionally identified within other lymphoproliferative lesions represent a reactive proliferation rather than a potentially aggressive second neoplasm.