Renal cell carcinoma, unclassified with medullary phenotype: poorly differentiated adenocarcinomas overlapping with renal medullary carcinoma.

Renal medullary carcinoma (RMC) is a highly aggressive renal cell carcinoma arising in the collecting system and requiring careful correlation with status of sickle cell trait. A panel of international experts has recently proposed provisional diagnostic terminology, renal cell carcinoma, unclassified, with medullary phenotype, based on encountering an extraordinarily rare tumor with RMC morphology and immunophenotype in an individual proven not to have a hemoglobinopathy. Herein, we extend this observation to a cohort of 5 such tumors, morphologically similar to RMC, lacking SMARCB1 expression by immunohistochemistry, but each without evidence of a hemoglobinopathy. The tumors arose in 4 men and 1 woman with a mean age of 44 years, occurring in 3 left and 2 right kidneys. Clinically, aggression was apparent with involvement of perinephric adipose tissue in all 5 cases, nodal metastasis in 4 of 5 cases, and death of disease in 4 of 5 cases within 3-27 months. Histologic sections showed poorly differentiated adenocarcinoma, often with solid and nested growth patterns, as well as infiltrative glandular, tubulopapillary, cribriform, or reticular growth. Rhabdoid and sarcomatoid cytomorphology was seen in a subset. All tumors showed PAX8 nuclear positivity and SMARCB1 loss, with OCT3/4 expression in 4 of 5 cases. In summary, this first series of renal cell carcinoma, unclassified, with medullary phenotype documents tumors with morphologic, immunophenotypic, and prognostic features of RMC occurring in individuals without sickle cell trait. Although greater biologic and molecular understanding is needed, the available evidence points to these cases representing a sporadic counterpart to sickle cell trait-associated RMC.

Cytokeratin 5/6 and P63 immunophenotype of thyroid lymphoepithelial complexes.

Thyroid lymphoepithelial complexes (LECos) are rare, being reported in lymphoma, Graves-Basedow disease, Hashimoto thyroiditis, pericarcinomatous thyroid or in the context of branchial cleft-like cysts. Here we report immunohistochemical expression of cytokeratin 5/6, P63 and TTF1 in 6 cases of thyroid LECos. Two cases had carbimazole treatment for hyperthyroidia and Graves disease. Anti-thyroglobulin, -thyroperoxidase or -TSH antibodies were detected in 4 cases. NSAID or poviodone iodine allergy were present in 2 cases. The treatment consisted in total thyroidectomy or lobectomy. Microscopy showed nodular goiter and focal lymphocytic thyroiditis. Basaloid LECos were seen in all thyroids while squamoid LECos in 2. Associated lesions were papillary thyroid microcarcinoma (2 cases), solid cell nest, thyroglosal duct remnant, lymphoepithelial cyst and thymus-parathyroid unit (one case each). Cytokeratin 5/6 was expressed in both squamoid and basaloid LECos along with P63. TTF1 expression was faint or absent. In conclusion LECos may occur in the context of autoimmune thyroiditis or of a specific immune susceptibility background. The expression of CK5/6 and of P63 suggests a squamous differentiation including in the basaloid LECos. The etiologic relevance of these immunostainings remains limited although rather suggestive of a metaplastic process than of migration-abnormalities.

Acute Appendicitis and Pneumatosis in a Duplicated Appendix With Schistosoma Remnants.

Appendiceal pneumatosis is rare, reported either in the context of acute appendicitis or enterocolitis. Here, we report the case of an elderly adult in whom the acute appendicitis was associated with pneumatosis and occurred in the context of a malformed appendix with pathogenic organism remnants. A 72-year-old man presented with abdominal pain 3 weeks after posttraumatic dorsolumbar surgery. The computed tomography scan showed acute appendicitis and 2 diverticula. On microscopy, the appendix showed acute appendicitis along with a Cave-Wallbridge type A duplication. In addition, several optically clear spaces were observed in the entire appendiceal wall consistent with pneumatosis of the appendix. Focally, calcified structures suggesting pathogenic organisms such as Schistosoma were noted as well. In conclusion, we report a case of appendiceal pneumatosis occurring in the context of acute appendicitis in a duplicated appendix, with presence of calcified structures suggestive of pathogenic organisms.

Dual Action of miR-125b As a Tumor Suppressor and OncomiR-22 Promotes Prostate Cancer Tumorigenesis.

MicroRNAs (miRs) are a novel class of small RNA molecules, the dysregulation of which can contribute to cancer. A combinatorial approach was used to identify miRs that promote prostate cancer progression in a unique set of prostate cancer cell lines, which originate from the parental p69 cell line and extend to a highly tumorigenic/metastatic M12 subline. Together, these cell lines are thought to mimic prostate cancer progression in vivo. Previous network analysis and miR arrays suggested that the loss of hsa-miR-125b together with the overexpression of hsa-miR-22 could contribute to prostate tumorigenesis. The dysregulation of these two miRs was confirmed in human prostate tumor samples as compared to adjacent benign glandular epithelium collected through laser capture microdissection from radical prostatectomies. In fact, alterations in hsa-miR-125b expression appeared to be an early event in tumorigenesis. Reverse phase microarray proteomic analysis revealed ErbB2/3 and downstream members of the PI3K/AKT and MAPK/ERK pathways as well as PTEN to be protein targets differentially expressed in the M12 tumor cell compared to its parental p69 cell. Relevant luciferase+3'-UTR expression studies confirmed a direct interaction between hsa-miR-125b and ErbB2 and between hsa-miR-22 and PTEN. Restoration of hsa-miR-125b or inhibition of hsa-miR-22 expression via an antagomiR resulted in an alteration of M12 tumor cell behavior in vitro. Thus, the dual action of hsa-miR-125b as a tumor suppressor and hsa-miR-22 as an oncomiR contributed to prostate tumorigenesis by modulations in PI3K/AKT and MAPK/ERK signaling pathways, key pathways known to influence prostate cancer progression.

NUT midline carcinoma presenting with bilateral ovarian metastases: a case report.

Nuclear protein of the testis (NUT) midline carcinoma (NMC) is an uncommon, relatively recently characterized carcinoma, which is defined by NUT gene rearrangements. We are reporting a case of NMC in a 38-year-old female who presented with pleural effusion and bilateral ovarian masses. We also discuss some of the difficulties encountered by the practicing pathologist in reaching the diagnosis and the role of ancillary studies. Immunohistochemical staining using a commercially available monoclonal antibody showing nuclear expression of the NUT protein is diagnostic of NMC. Dual-color split-apart fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) can be used to characterize the fusion gene, whether BRD4-NUT or BRD3-NUT, or NUT-variant.

Do Osteoblastoma and Osteoid Osteoma Represent the Same Pathologic Entity?: A Case Report and Review of the Recent Literature.

CASE: We present the case of a fourteen-year-old boy with a benign diaphyseal femoral lesion that initially fulfilled the diagnostic criteria for osteoid osteoma but rapidly progressed and was finally diagnosed as osteoblastoma. CONCLUSION: Clinical and radiographic criteria provide imperfect and somewhat arbitrary distinguishing features between osteoid osteoma and osteoblastoma. Although previous work highlighted the importance of histologic interpretation in this regard, recent comparative histologic and immunohistochemical evaluations failed to differentiate the two. We conclude that consideration should be given to the classification of osteoid osteoma and osteoblastoma as the same pathologic entity, with treatment based on presentation along a continuum of aggressiveness, and that future directions for study may include identification of factors predictive of progression and/or recurrence.

The role of cystectomy for non-malignant bladder conditions: a review.

INTRODUCTION: Few studies have adequately addressed the indications, efficacy, and quality-of-life for cystectomy performed for non-malignant bladder conditions. Patients with debilitating non-malignant bladder conditions who have failed all previous conservative therapies may undergo various forms of cystectomy, including partial, simple or radical cystectomy. We provide a review of the current literature and recommendations for cystectomy for various non-malignant bladder conditions. MATERIALS AND METHODS: A systematic review of MEDLINE was conducted to find prospective and retrospective studies using the keywords "cystectomy", "benign", and `non-malignant`. Articles were reviewed and triaged, background articles were added as supplements, leaving a final review of 67 papers. RESULTS: Data from the final review suggests that common benign indications for cystectomy are interstitial cystitis/painful bladder syndrome (IC/PBS), neurogenic bladder, hemorrhagic/radiation cystitis, infectious diseases of the bladder and miscellaneous conditions of the bladder such as endometriosis and total refractory incontinence. The most common perioperative complications include urinary tract and wound infections. Efficacy of cystectomy in patients with IC/PBS is greater than 80%, while efficacy in patients with neurogenic bladder is greater than 90%. Finally, improved urinary quality-of-life has been demonstrated in patients with neurogenic bladder post-cystectomy. CONCLUSION: Cystectomy for non-malignant conditions can be considered for patients who have failed previous conservative therapy. The limited data in existence suggests fertility can be adequately preserved after cystectomy in younger males. The data regarding the forms of urinary diversion suggests no significant advantage between any of the major forms of urinary diversion. Finally, while newer pharmacologics and technological advances are widely used in the treatment of various benign urological conditions, their role in preventing or treating refractory benign bladder conditions have not been fully characterized.

Indications for renal fine needle aspiration biopsy in the era of modern imaging modalities.

BACKGROUND: Renal fine needle aspiration biopsy (FNAB) has become an uncommon procedure in the era of renal helical computed tomography (CT), which has high diagnostic accuracy in the characterization of renal cortical lesions. This study investigates the current indications for renal FNAB. Having knowledge of the specific clinico-radiologic scenario that led to the FNAB, cytopathologists are better equipped to expand or narrow down their differential diagnosis. MATERIALS AND METHODS: All renal FNABs performed during a 6 year interval were retrieved. Indication for the procedure was determined from the clinical notes and radiology reports. RESULTS: Forty six renal FNABs were retrieved from 43 patients (14 females and 29 males with a mean age of 52 years [range, 4-81 years]). Twenty one cases (45.6%) were performed under CT-guidance and 25 cases (54.4%) under US-guidance. There were four distinct indications for renal FNAB: (1) solid renal masses with atypical radiological features or poorly characterized on imaging studies due to lack of intravenous contrast or body habitus (30.2%); (2) confirmation of radiologically suspected renal cell carcinoma in inoperable patients (advanced stage disease or poor surgical candidate status) (27.9%); (3) kidney mass in a patient with a prior history of other malignancy (27.9%); and (4) miscellaneous (drainage of abscess, indeterminate cystic lesion, urothelial carcinoma) (14.0%). 36 patients (83.7%) received a specific diagnosis based on renal FNAB cytology. CONCLUSIONS: Currently, renal fine needle aspiration remains a useful diagnostic tool in selected clinico-radiologic scenarios.

Pericardial fluid cytology: an analysis of 128 specimens over a 6-year period.

BACKGROUND: Pericardial fluid (PF) accumulates through various mechanisms and cytology is part of the workup to determine the specific etiology, primarily to rule in or rule out malignancy. To the best of the authors' knowledge, the current study is the largest systematic evaluation of PF cytology performed to date. METHODS: PF specimens collected over 6 years were retrieved. Clinical history, laboratory, cytologic, and pericardial biopsy results were recorded. RESULTS: A total of 128 PF specimens were obtained from 113 patients (56 males and 57 females), representing 4.5% of all fluids. Of these, 95 cases (74.2%) were benign, 2 (1.6%) had "severely atypical cells, " and 31 cases (24.2%) were malignant. The most common etiologies for benign PF specimens were neoplasm (23.1%), idiopathic (19%), infection (14.7%), and connective tissue disease (12.6%). The most common neoplasm producing malignant PF was lung carcinoma, both in males (75%) and females (52.2%), with adenocarcinoma being the most common type (72.2%). In females, breast carcinoma was the second most common neoplasm (39.1%). Approximately 87.1% of patients with malignant PF specimens had a prior history of malignancy and approximately 32.7% underwent a concomitant pericardial biopsy. The false-negative rate for cytology was 14.7% (hematologic malignancies [2 cases], metastatic sarcoma [1 case], and sarcoidosis [1 case] not detected) and that for pericardial biopsy was 40% (metastatic carcinoma [4 cases] not detected). CONCLUSIONS: PF specimens are uncommon. A specific interpretation is rendered in approximately 98.4% of cases. Lung carcinoma is the most common tumor to produce malignant PF in both males and females. Approximately 87.1% of patients with malignant PF have a known history of malignancy. Although cytology is superior to pericardial biopsy in diagnosing metastatic carcinoma, other tumors may go undetected in the PF.

Small cell osteosarcoma with Ewing sarcoma breakpoint region 1 gene rearrangement detected by interphase fluorescence in situ hybridization.

Because of its characteristic morphologic appearance, small cell osteosarcoma (SCO) can be confused with other small round cell malignancies of the bone, most importantly with Ewing sarcoma, making this distinction difficult. A specific tool used in separating SCO from Ewing sarcoma has been the detection of Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangements in Ewing sarcoma and their absence in SCO. However, there are rare case reports that have documented the existence of EWSR1 gene rearrangement in SCO. In this report, we describe another case of SCO with an EWSR1 gene rearrangement detected by interphase fluorescence in situ hybridization. Our finding adds support to the existing evidence that SCO is a tumor that can be characterized by EWSR1 gene arrangements. Therefore, we caution the pathology community not to rely solely on molecular studies in distinguishing SCO from Ewing sarcoma.

Preservation of fine-needle aspiration specimens for future use in RNA-based molecular testing.

BACKGROUND: The application of ancillary molecular testing is becoming more important for the diagnosis and classification of disease. The use of fine-needle aspiration (FNA) biopsy as the means of sampling tumors in conjunction with molecular testing could be a powerful combination. FNA is minimally invasive, cost effective, and usually demonstrates accuracy comparable to diagnoses based on excisional biopsies. Quality control (QC) and test validation requirements for development of molecular tests impose a need for access to pre-existing clinical samples. Tissue banking of excisional biopsy specimens is frequently performed at large research institutions, but few have developed protocols for preservation of cytologic specimens. This study aimed to evaluate cryopreservation of FNA specimens as a method of maintaining cellular morphology and ribonucleic acid (RNA) integrity in banked tissues. METHODS: FNA specimens were obtained from fresh tumor resections, processed by using a cryopreservation protocol, and stored for up to 27 weeks. Upon retrieval, samples were made into slides for morphological evaluation, and RNA was extracted and assessed for integrity by using the Agilent Bioanalyzer (Agilent Technologies, Santa Clara, Calif). RESULTS: Cryopreserved specimens showed good cell morphology and, in many cases, yielded intact RNA. Cases showing moderate or severe RNA degradation could generally be associated with prolonged specimen handling or sampling of necrotic areas. CONCLUSIONS: FNA specimens can be stored in a manner that maintains cellular morphology and RNA integrity necessary for studies of gene expression. In addition to addressing quality control (QC) and test validation needs, cytology banks will be an invaluable resource for future molecular morphologic and diagnostic research studies.

Extranodal rosai-dorfman disease presenting as incidental bone tumor: a case report.

We report a case of primary extranodal Rosai-Dorfman disease presenting as a painless lesion in the left ilium of a 71-year-old African-American man.

MicroRNA-17-3p is a prostate tumor suppressor in vitro and in vivo, and is decreased in high grade prostate tumors analyzed by laser capture microdissection.

MicroRNAs (miRs) are a novel class of RNAs with important roles in regulating gene expression. To identify miRs controlling prostate tumor progression, we utilized unique human prostate sublines derived from the parental P69 cell line, which differ in their tumorigenic properties in vivo. Grown embedded in laminin-rich extracellular matrix (lrECM) gels these genetically-related sublines displayed drastically different morphologies correlating with their behaviour in vivo. The non-tumorigenic P69 subline grew as multicellular acini with a defined lumen and basal/polar expression of relevant marker proteins. M12, a highly tumorigenic, metastatic derivative, grew as a disorganized mass of cells with no polarization, whereas the F6 subline, a weakly tumorigenic, non-metastatic M12 variant, reverted to acini formation akin to the P69 cell line. These sublines also differed in expression of vimentin, which was high in M12, but low in F6 and P69 sublines. Analysis of vimentin's conserved 3'-UTR suggested several miRs that could regulate vimentin expression. The lack of miR-17-3p expression correlated with an increase in vimentin synthesis and tumorigenicity. Stable expression of miR-17-3p in the M12 subline reduced vimentin levels 85% and reverted growth to organized, polarized acini in lrECM gels. In vitro motility and invasion assays suggested a decrease in tumorigenic behaviour, confirmed by reduced tumor growth in male athymic, nude mice dependent on miR-17-3p expression. Analysis of LCM-purified clinical human prostatectomy specimens confirmed that miR-17-3p levels were reduced in tumor cells. These results suggest that miR-17-3p functions as a tumor suppressor, representing a novel target to block prostate tumor progression.