Kristian T. Schafernak

Classification of Renal Neoplasms Based on Molecular Signatures

PURPOSE Gene expression microarray studies have demonstrated distinct molecular signatures for different types of renal neoplasms based on overall gene expression patterns. However, in most of these studies the investigators used renal tumors with defined histology. We analyzed a test set of renal tumors in double-blind fashion using recently established molecular profiles of renal tumors as benchmarks. MATERIALS AND METHODS A total of 16 consecutive nephrectomies performed for neoplasms at a single urological service were subjected to gene expression profiling using cDNA chips containing 21,632 genes. Analysis was clustered with our previously established molecular profiles of 91 histologically defined kidney neoplasms and comparative genomic microarray analysis while blinded to tumor histology and clinical information. RESULTS With molecular analysis 9, 4, 2 and 1 tumors were classified as clear cell, papillary RCC, chromophobe RCC, and renal oncocytoma, respectively. Histopathological evaluation was concordant in 14 tumors. One of the 2 tumors with a discrepancy between molecular and pathological diagnoses was composed of oncocytoma and high grade clear cell RCC, and the other was chromophobe RCC that histologically mimicked papillary RCC. CONCLUSIONS We report the feasibility of the molecular diagnosis and classification of unknown renal neoplasms. Molecular diagnosis appears to be reliable and comparable to the standard of urological pathology. This molecular method may be a potentially useful test for establishing an accurate diagnosis that can impact clinical management.

Coronin-1A: Immune Deficiency in Humans and Mice

Since the discovery of coronins in 1991 significant research has been carried out to understand their molecular structure and cellular mechanisms of the action. While a number of binding partners have been discovered, the precise mechanisms of action of Coronin-1A are still being elucidated, both in vitro and in vivo. The role of Coronin-1A in the development and function of the immune system is irrefutable, in both humans and mice, and deficiency of Coronin-1A results in CID. Although some immunological manifestations of Coronin-1A deficiency differed between the patients described so far, absence of Coronin-1A affected the T cell compartment in all patients. B cell numbers were lower than normal and antibody responses were impaired. Variable NK cell defects associated with absent Coronin-1A to date will require detailed analysis of further patients. HCT was curative for patients with Coronin-1A deficiency when the disease was diagnosed early, before onset of irreversible complications arising from infections and EBV associated malignancy. With new evidence about the potential of anti-Coronin-1A monoclonal antibodies to treat B cell malignancies and T cell-mediated auto-inflammatory diseases, Coronin-1A can now be said to be involved in the overall regulation of the immune system, and inappropriate expression can lead to either immune deficiency or autoimmunity.

Clonality assessment of cutaneous B-cell lymphoid proliferations: A comparison of flow cytometry immunophenotyping, molecular studies, and immunohistochemistry/in situ hybridization and review of the literature

Abstract:Cutaneous lymphoid infiltrates are diagnostically challenging. Although ancillary techniques to assess clonality can help distinguish between reactive lymphoid hyperplasia and lymphoma, one of the most widely used techniques in hematopathology, flow cytometry immunophenotyping (FCI), has not been routinely applied to skin specimens. We performed FCI on 73 skin specimens from 67 patients clinically suspected of having a cutaneous B-cell lymphoma (CBCL) and compared the results with those obtained from immunoglobulin heavy chain (IGH) gene molecular studies (58 cases, primarily by polymerase chain reaction) and either immunohistochemistry (IHC) or in situ hybridization to evaluate for light chain restriction (22 and 2 cases, respectively). Sufficient quantity of CD45 (leukocyte common antigen)-positive cells and staining quality were achieved in 88% of cases by FCI, and clonality was detected in 68% of CBCLs versus molecular studies showing sufficient DNA quality in 74% and only 39% clonality detection, and interpretable/contributory IHC results in 84% of cases with 55% clonality detection. Clonality was documented more frequently in secondary rather than primary CBCLs by all 3 techniques. Therefore, FCI is feasible and appears to be more reliable than molecular studies or IHC/in situ hybridization for detecting clonality in CBCLs and can provide additional prognostically and therapeutically relevant information. The exception is cases with plasmacytic differentiation such as marginal zone lymphoma for which IHC might be a superior tool. We have also shown that a large subset of primary cutaneous follicle center lymphomas express CD10 and/or BCL2 by FCI. Recent advances in FCI beg the question of applicability to cutaneous T-cell and NK–cell lymphomas.

Cytologic and histologic findings in multiple renal hybrid oncocytic tumors in a patient with Birt-Hogg-Dubé syndrome: a case report.

BACKGROUND Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant neoplastic syndrome characterized by multiple skin lesions, lung cysts and renal tumors. A variety of histologic types of renal tumors have been reported, including clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, oncocytoma and a recently described hybrid oncocytic tumor, which is thought to be highly associated with BHD. CASE We report a case of a 48-year-old woman with BHD who initially presented to our institution with spontaneous pneumothorax and was found to have multiple lung cysts and renal tumors on computed tomography. We describe the fine needle aspiration findings of one of the renal tumors, which was suggestive of so-called hybrid oncocytic tumor. We also describe the gross and histologic findings of the multiple kidney tumors that the patient subsequently had excised. CONCLUSION When multiple kidney tumors from a single patient appear oncycytic on fine needle aspiration, especially when focal clear cells are present, the possibility of oncocytomas and hybrid tumors associated with BHD must be entertained.

Does 'granular cell' renal cell carcinoma exist? Molecular and histological reclassification.

trates alone (n 1⁄4 18), the proportion of TdT+ cases was 50% (n 1⁄4 9). None of the remaining neuroendocrine tumours under investigation revealed TdT positivity. In routine histopathological practice, immunohistochemical detection of TdT is widely used as a marker for lymphoblastic leukaemias and lymphomas. However, as reported by Mathewson et al., TdT is also detectable by immunohistochemistry in a significant number of paediatric small round cell tumours. Our study furthermore extends the spectrum of tumours with possible TdT positivity. The functional role of TdT in MCC remains unclear. The gene coding for the TdT protein has been mapped to chromosome 10q. Interestingly, comparative genomic hybridization studies in MCC have revealed a number of chromosomal imbalances, including losses on chromosome 10, in 33% of cases. It is tempting to speculate that this frequent aberration might be causally related to aberrant TdT protein expression. Future molecular analyses are needed to elucidate this issue. An important consequence of the reported observation is that TdT positivity cannot be regarded as sufficient for the differential diagnosis of lymphoblastic lymphoma and MCC, which are often difficult to distinguish by morphology alone. In this regard it should be mentioned that even the B-cell transcription factor PAX5, whose expression was thought to be restricted to B cells, has also recently been shown to be expressed in most MCCs. The diagnosis of MCC should therefore be based on the demonstration of cytokeratin expression. Our results also indicate that TdT expression in MCC may serve as an additional immunohistochemical discriminator in the differential diagnosis form non-cutaneous neuroendocrine tumours.

Rare Presentations of Epstein-Barr Virus–Associated Smooth Muscle Tumor in Children

Epstein-Barr virus (EBV) has oncogenic potential and has been implicated in the etiology of a wide range of malignancies. Certain EBV-driven neoplasms, such as smooth muscle tumors (SMTs), manifest typically in immunocompromised patients. In children, these neoplasms have been encountered in the setting of primary immune disorders, specifically severe combined and common variable immunodeficiency syndromes. Human immunodeficiency virus infection and posttransplant immunosuppression, in particular liver and kidney transplantation, likewise increase the risk in the pediatric population. The location of these neoplasms appears related to the type of immunodeficiency: in acquired immunodeficiency syndrome they are frequently located intracranially or intraspinally, whereas after transplant they usually involve the liver or lung. We report 2 distinct cases of EBV-related SMT, unique through their coassociated immunosuppressive state or location: the 1st occurred in a patient with immunodeficiency secondary to NEMO gene mutation following hematopoietic stem cell transplantation; the 2nd developed in the orbit after heart transplant.

Gelatinous transformation of the bone marrow from anorexia nervosa

![Figure][1] A 16-year-old girl with X-linked hypophosphatemic rickets, anorexia nervosa, and rumination syndrome with severe malnutrition underwent bone marrow examination for leukopenia (2.03 × 109/L), mildly macrocytic anemia (hemoglobin, 106 g/L; mean corpuscular volume, 99.3 fL), and

Deconstructing the diagnosis of hemophagocytic lymphohistiocytosis using illustrative cases

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of extreme inflammation occurring in association with genetic defects involving the granule-dependent cytotoxic pathway of CD8+ T cells or NK cells and/or a wide variety of triggers including infections, malignancies, and rheumatologic disorders. Because of its relative rarity and the non-specific nature of the individual clinical and laboratory abnormalities comprising the characteristic “pattern” of HLH, the diagnosis can be elusive. Furthermore, some of the laboratory tests included in the diagnostic criteria are time-consuming or not widely available, and since many of these patients are critically ill, HLH must be considered early on so that the diagnosis can be established and potentially life-saving treatment initiated. Since the diagnosis of HLH is truly a clinicopathologic correlation, in this article, we as a team of pediatric clinical and laboratory physicians will use exemplary cases from our own institution with a variety of clinical presentations to illustrate the many “faces” of HLH; deconstruct the diagnosis; point out some of the challenges, limitations, pearls and pitfalls; and make it easier to understand the pathophysiology in context. However, while we may see relatively more cases working in a tertiary care children’s hospital, HLH is a disease of both children and adults.

Pulmonary langerhans cell histiocytosis: Historical context and current concepts

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease seen as part of multisystem Langerhans cell histiocytosis, or as an isolated form of the disease. The majority of cases of the latter are seen in adults and associated with cigarette smoking, which probably plays a central etiologic role. Although the mechanisms leading to the development of isolated PLCH are unclear, it is thought to be a reactive process in contrast to other forms of Langerhans cell histiocytosis, which have been shown to represent clonal, neoplastic proliferations of Langerhans cells. Isolated PLCH and the other forms may be altogether separate diseases, but they have in common great variability in severity and, likewise, unpredictable clinical courses. In this article, we provide an historical context for these elusive diseases, as well as summarize the most recent literature on PLCH.

Hermansky-Pudlak syndrome: Report of two patients with updated genetic classification and management recommendations

Hermansky‐Pudlak syndrome (HPS) is a rare autosomal recessive disorder caused by mutations in one of nine genes involved in the packaging and formation of specialized lysosomes, including melanosomes and platelet‐dense granules. The cardinal features are pigmentary dilution, bleeding diathesis, and accumulation of ceroid‐like material in reticuloendothelial cells. Pulmonary fibrosis induced by tissue damage is seen in the most severe forms, and one subtype is characterized by immunodeficiency. We describe two patients with HPS type 1 and review the updated gene‐based classification, clinical features, and recommendations for evaluation and follow‐up.