Cytoplasmic Fibrils Research Articles

Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry

Rare, sporadic uterine leiomyomas arise in the setting of severe metabolic aberration due to a somatic fumarate hydratase mutation. Germline mutations account for the hereditary leiomyomatosis and renal cell carcinoma syndrome, which predisposes for cutaneous and uterine leiomyomas and aggressive renal cell carcinomas. Altered fumarate hydratase leads to fumarate accumulation in affected cells with formation of S-(2-succino)-cysteine, which can be detected with the polyclonal antibody. High levels of these modified cysteine residues are found characteristically in fumarate hydratase-deficient cells but not in normal tissues or tumors unassociated with hereditary leiomyomatosis and renal cell carcinoma syndrome. We hypothesized that S-(2-succino)-cysteine-positive leiomyomas, indicating fumarate hydratase aberration, have morphologic features that differ from those without S-(2-succino)-cysteine positivity. Hematoxylin and eosin-stained slides of uterine smooth-muscle tumors were prospectively analyzed for features suggesting hereditary leiomyomatosis and renal cell carcinoma syndrome, such as prominent eosinophilic macronucleoli with perinucleolar halos, yielding nine cases. Germline genetic testing for fumarate hydratase mutations was performed in three cases. A detailed morphological analysis was undertaken, and S-(2-succino)-cysteine immunohistochemical analysis was performed with controls from a tissue microarray (leiomyomas (19), leiomyosarcomas (29), and endometrial stromal tumors (15)). Of the nine study cases, four had multiple uterine smooth muscle tumors. All cases had increased cellularity, staghorn vasculature, and fibrillary cytoplasm with pink globules. All cases had inclusion-like nucleoli with perinuclear halos (7 diffuse, 1 focal). All showed diffuse granular cytoplasmic labeling with the S-(2-succino)-cysteine antibody. Two of three tested patients had germline fumarate hydratase mutations. Only one leiomyoma from the tissue microarray controls was immunohistochemically positive, and it showed features similar to other immunohistochemically positive cases. Smooth-muscle tumors with fumarate hydratase aberration demonstrate morphological reproducibility across cases and S-(2-succino)-cysteine immuno-positivity. Although the features described are not specific for the germline fumarate hydratase mutation or the hereditary leiomyomatosis and renal cell carcinoma syndrome, their presence should suggest fumarate hydratase aberration. Identifying these cases is an important step in the diagnostic workup of patients with possible hereditary leiomyomatosis and renal cell carcinoma.

Ovarian Paraganglioma

A rare case of ovarian paraganglioma was incidentally found as a 1.2-cm intraovarian mass in a 68-year-old hypertensive female operated for an endometrial carcinoma. Histologically, it was arranged in characteristic Zellballen composed of polygonal clear cells with a granular cytoplasm that expressed diffusely CAM5.2 cytokeratin, chromogranin, neuron-specific enolase, synaptophysin, and CD56, while S-100 protein was only present in sustentacular cells. We analyzed differential diagnoses with other rare ovarian tumors such as Sertoli cell tumor, with which it may share an immunophenotype expressing cytokeratins, S-100, and other neural markers, and extra-axial ependymoma, which invariably expresses diffusely GFAP, that may be positive only in the sustentacular cells of paraganglioma. However, on simple hematoxylin-eosin inspection, ovarian paraganglioma displays characteristic Zellballen clusters and cells with a granular cytoplasm but lacks the distinctive Sertoli cell tubules and the characteristic rosettes and fibrillary cytoplasm of ependymoma. Pathologists should be aware of the unusual locations of paraganglioma.

Treatment of Ovarian Anaplastic Ependymoma by an Aromatase Inhibitor

Histopathologic diagnosis and treatment of ovarian anaplastic ependymoma are challenging. A 61-year-old-woman presented with a 10-cm right adnexal tumor associated with peritoneal carcinomatosis extending to the right diaphragm and liver surface. After initial diagnosis of a papillary serous carcinoma, we performed extensive but nonoptimal cytoreductive surgery including hysterectomy with bilateral oophorectomy. Histology revealed some axially arranged cells with a prominent fibrillary cytoplasm, suggesting an ependymoma. Diagnosis was confirmed by immunophenotype showing strong positivity to glial fibrillary acidic protein. Given the strong tumoral expression of estrogen and progesterone receptors, an aromatase inhibitor was initiated. One year later, computed tomography scan showed stability of the residual peritoneal nodules. Aromatase inhibitor treatment could be effective in cases of extraaxial ependymoma with prominent estrogen receptor expression.

Primary anterior abdominal wall leiomyoma- a diagnostic enigma.

Primary anterior abdominal wall leiomyoma- a diagnostic enigma.

Breast leiomyoma: a case report and review of the literature

Breast leiomyoma is a rare and benign tumor which arises from a smooth muscle in nipple and areola or smooth muscle metaplasia of myoepithelial cells or myofibroblastic cells. Common differential diagnosis of the breast leiomyoma was as follows: fibroadenoma, myoepithelioma, phyllodes tumor, and leiomyosarcoma. We present here a rare case of solitary leiomyoma of the breast. We described a case of breast leiomyoma diagnosed in an otherwise healthy 37-year-old woman at the Rajaee Hospital. The patient presented with a palpable mass in her right breast since 2 years. Physical examination showed a mobile and smooth mass, without any axillary lymphadenopathy. The radiologic examinations revealed a well-circumscribed ovoid mass, 5 cm in diameter. Excisional biopsy disclosed a well-circumscribed cellular tumor by interlacing fascicles of spindle cells with fibrillary and eosinophilic cytoplasm. The tumoral cells were immunoreactive for smooth muscle actin. There were not any evidences of disease recurrence for 20 months of follow up. Histopathological study and immunohistochemical examinations help in the discrimination between leiomyoma and other benign and malignant breast lesions and determination of outcome.

Pituicytoma with Gelsolin Amyloid Deposition

Pituicytoma is a rare low-grade (WHO grade I) sellar region glioma. Among sellar tumors, pituitary adenomas, mainly prolactinomas, may show amyloid deposits. Gelsolin is a ubiquitous calcium-dependent protein that regulates actin filament dynamics. Two known gene point mutations result in gelsolin amyloid deposition, a characteristic feature of a rare type of familial amyloid polyneuropathy (FAP), the Finnish-type FAP, or hereditary gelsolin amyloidosis (HGA). HGA is an autosomal-dominant systemic amyloidosis, characterized by slowly progressive neurological deterioration with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A unique case of pituicytoma with marked gelsolin amyloid deposition in a 67-year-old Chinese woman is described. MRI revealed a 2.6-cm well-circumscribed, uniformly contrast-enhancing solid sellar mass with suprasellar extension. Histologically, the lesion was characterized by solid sheets and fascicles of spindle cells with slightly fibrillary cytoplasm and oval nuclei with pinpoint nucleoli. Surrounding brain parenchyma showed marked reactive piloid gliosis. Remarkably, conspicuous amyloid deposits were identified as pink homogeneous spherules on light microscopy that showed apple-green birefringence on Congo red with polarization. Mass spectrometric-based proteomic analysis identified the amyloid as gelsolin type. Immunohistochemically, diffuse reactivity to S100 protein and TTF1, focal reactivity for GFAP, and no reactivity to EMA, synaptophysin, and chromogranin were observed. HGA-related mutations were not identified in the tumor. No recurrence was noted 14 months after surgery. To the knowledge of the authors, amyloid deposition in pituicytoma or tumor-associated gelsolin amyloidosis has not been previously described. This novel finding expands the spectrum of sellar tumors that may be associated with amyloid deposition.

Evaluation of the Effects of a Moderate Intensity Static Magnetic Field Application on Human Osteoblast-Like Cells

There is a general interest in the effects of magnetic fields on human tissue, for biomedical imaging, cancer therapy or tissue engineering applications. In particular the orthopaedic field may greatly benefit from magnetic scaffolds, magnetic fixation and magnetic delivery techniques. In this study, MG-63 osteoblast-like cells were analysed <i>in vitro</i> after exposure to a 320mT static magnetic field (SMF), either continuously or applied for 1h at any 24-hour interval. Results demonstrate that SMF causes a reduction in cell number after 7 days of exposure, as demonstrated by the MTT assay. This reduction in proliferation is not associated to an increase in Lactate Dehydrogenase production, a marker of cellular stress and/or disruption of membrane integrity. Osteocalcin secretion increased at day 3 for the condition 1h/day exposure and this effect was reversed after 7 days. Instead, the continuous application of a SMF resulted in a significantly decreased osteocalcin release at day 7. Cell distribution, morphology and cytoskeleton organization were unaltered, with the typical osteoblastic morphology maintained and normal distribution of cytoplasmic actin fibrils, as demonstrated by phalloidin staining. Gene expression analysis of COL1A1, ALPL and RUNX2 show no alterations respect to control. These results suggest that such a moderate intensity static magnetic field has a detrimental effect on cell proliferation and osteocalcin secretion, while maintaining morphological features and gene expression unaltered. The <i>in vitro</i> effects of magnetic fields depend on cell type, magnetic field intensity and modality of application. This study gives a contribution to understand moderate strength static magnetic field effects on human tissue, with particular importance for the orthopaedic field.

Human immunodeficiency virus type 1 infection alters enzymatic and ultrastructural features of peripheral blood monocytes

INTRODUCTION:Human immunodeficiency virus-1 (HIV-1) infected monocytes are now believed to serve as a reservoir for HIV-1 infection, and to play a role in viral rebound phenomena in certain groups of patients who failed or stopped highly active antiretroviral therapy (HAART). Data characterizing the morphological changes of peripheral blood monocytes in HIV-1-infected individuals are limited.MATERIALS AND METHODS:In this study, we collected monocytes from 21 asymptomatic HIV-1-infected individuals with CD4 count more than 500 cells/mm3 and healthy individuals. The monocytes ultrastructural morphologic changes and α-naphthyl butyrate esterase (ANBE) activity were compared between the two groups.RESULTS:In monocytes from patients infected with HIV-1, activity of α-naphthyl butyrate esterase (ANBE) was markedly increased compared with normal monocytes. In both light microscopic and ultrastructural studies, the cytoplasm of monocytes from HIV-1-infected patients contained a haphazard appearing network of thin fibrils. Cell surface expression of the activation marker HLA-DR molecule was upregulated. There were no discernible differences between the cell surface expression of CD4, CD14, and CD16 molecules comparing normal monocytes to those from HIV-1-infected patients. α-naphthyl butyrate esterase (ANBE) was markedly increased compared with normal monocytes. In both light microscopic and ultrastructural studies, the cytoplasm of monocytes from HIV-1-infected patients contained a haphazard appearing network of thin fibrils. Cell surface expression of the activation marker HLA-DR molecule was upregulated. There were no discernible differences between the cell surface expression of CD4, CD14, and CD16 molecules comparing normal monocytes to those from HIV-1-infected patients.CONCLUSIONS:Possibly, changes in the activity of ANBE along with a disrupted appearing cytoplasmic fibril network contribute to monocyte dysfunction in HIV-1-infected patients.

The Oncogene eIF4E Reprograms the Nuclear Pore Complex to Promote mRNA Export and Oncogenic Transformation

The eukaryotic translation initiation factor eIF4E is a potent oncogene that promotes the nuclear export and translation of specific transcripts. Here, we have discovered that eIF4E alters the cytoplasmic face of the nuclear pore complex (NPC), which leads to enhanced mRNA export of eIF4E target mRNAs. Specifically, eIF4E substantially reduces the major component of the cytoplasmic fibrils of the NPC, RanBP2, relocalizes an associated nucleoporin, Nup214, and elevates RanBP1 and the RNA export factors, Gle1 and DDX19. Genetic or pharmacological inhibition of eIF4E impedes these effects. RanBP2 overexpression specifically inhibits the eIF4E mRNA export pathway and impairs oncogenic transformation by eIF4E. The RanBP2 cytoplasmic fibrils most likely slow the release and/or recycling of critical export factors to the nucleus. eIF4E overcomes this inhibitory mechanism by indirectly reducing levels of RanBP2. More generally, these results suggest that reprogramming the NPC is a means by which oncogenes can harness the proliferative capacity of the cell.

Structure of a Yeast Dyn2-Nup159 Complex and Molecular Basis for Dynein Light Chain-Nuclear Pore Interaction

The nuclear pore complex gates nucleocytoplasmic transport through a massive, eight-fold symmetric channel capped by a nucleoplasmic basket and structurally unique, cytoplasmic fibrils whose tentacles bind and regulate asymmetric traffic. The conserved Nup82 complex, composed of Nsp1, Nup82, and Nup159, forms the unique cytoplasmic fibrils that regulate mRNA nuclear export. Although the nuclear pore complex plays a fundamental, conserved role in nuclear trafficking, structural information about the cytoplasmic fibrils is limited. Here, we investigate the structural and biochemical interactions between Saccharomyces cerevisiae Nup159 and the nucleoporin, Dyn2. We find that Dyn2 is predominantly a homodimer and binds arrayed sites on Nup159, promoting the Nup159 parallel homodimerization. We present the first structure of Dyn2, determined at 1.85 Å resolution, complexed with a Nup159 target peptide. Dyn2 resembles homologous metazoan dynein light chains, forming homodimeric composite substrate binding sites that engage two independent 10-residue target motifs, imparting a β-strand structure to each peptide via antiparallel extension of the Dyn2 core β-sandwich. Dyn2 recognizes a highly conserved QT motif while allowing sequence plasticity in the flanking residues of the peptide. Isothermal titration calorimetric analysis of the comparative binding of Dyn2 to two Nup159 target sites shows similar affinities (18 and 13 μM), but divergent thermal binding modes. Dyn2 homodimers are arrayed in the crystal lattice, likely mimicking the arrayed architecture of Dyn2 on the Nup159 multivalent binding sites. Crystallographic interdimer interactions potentially reflect a cooperative basis for Dyn2-Nup159 complex formation. Our data highlight the determinants that mediate oligomerization of the Nup82 complex and promote a directed, elongated cytoplasmic fibril architecture.

Insights into mRNP biogenesis provided by new genetic interactions among export and transcription factors

BackgroundThe various steps of mRNP biogenesis (transcription, processing and export) are interconnected. It has been shown that the transcription machinery plays a pivotal role in mRNP assembly, since several mRNA export factors are recruited during transcription and physically interact with components of the transcription machinery. Although the shuttling DEAD-box protein Dbp5p is concentrated on the cytoplasmic fibrils of the NPC, previous studies demonstrated that it interacts physically and genetically with factors involved in transcription initiation.ResultsWe investigated the effect of mutations affecting various components of the transcription initiation apparatus on the phenotypes of mRNA export mutant strains. Our results show that growth and mRNA export defects of dbp5 and mex67 mutant strains can be suppressed by mutation of specific transcription initiation components, but suppression was not observed for mutants acting in the very first steps of the pre-initiation complex (PIC) formation.ConclusionsOur results indicate that mere reduction in the amount of mRNP produced is not sufficient to suppress the defects caused by a defective mRNA export factor. Suppression occurs only with mutants affecting events within a narrow window of the mRNP biogenesis process. We propose that reducing the speed with which transcription converts from initiation and promoter clearance to elongation may have a positive effect on mRNP formation by permitting more effective recruitment of partially-functional mRNP proteins to the nascent mRNP.

Primary Intranodal Epithelioid Rhabdomyosarcoma

We report an unusual, rare case of primary epithelioid rhabdomyosarcoma of a lymph node in the parotid basin. A 72-year-old man with a history of squamous cell carcinoma of the forehead and cheek had a 5-cm mobile nontender mass of the parotid tail and right level II region. A positron emission tomography/computed tomography scan confirmed a hypermetabolic soft tissue mass in the right parotid gland. Histologic sections showed an intraparotid lymph node almost completely effaced by a centrally necrotic malignant epithelioid neoplasm consisting of uniform-appearing dyshesive cells exhibiting rhabdoid morphologic features with abundant eosinophilic fibrillary cytoplasm, eccentric nuclei, and prominent nucleoli. Bizarre cells were not seen. In immunohistochemical studies, neoplastic cells expressed desmin and myogenin. Electron microscopy showed a mixture of thick and thin filaments, primitive Z-band formation, and well-formed sarcomeres. Fluorescence in situ hybridization studies for FOXO1, PAX3, and/or PAX7 rearrangements were negative. An extensive clinical and radiologic workup showed no evidence of primary tumor elsewhere. Complete resection of the tumor was performed, and adjuvant chemotherapy was given; patient was disease free 12 months after surgery.

Ran-dependent docking of importin-β to RanBP2/Nup358 filaments is essential for protein import and cell viability

RanBP2/Nup358, the major component of the cytoplasmic filaments of the nuclear pore complex (NPC), is essential for mouse embryogenesis and is implicated in both macromolecular transport and mitosis, but its specific molecular functions are unknown. Using RanBP2 conditional knockout mouse embryonic fibroblasts and a series of mutant constructs, we show that transport, rather than mitotic, functions of RanBP2 are required for cell viability. Cre-mediated RanBP2 inactivation caused cell death with defects in M9- and classical nuclear localization signal (cNLS)-mediated protein import, nuclear export signal-mediated protein export, and messenger ribonucleic acid export but no apparent mitotic failure. A short N-terminal RanBP2 fragment harboring the NPC-binding domain, three phenylalanine-glycine motifs, and one Ran-binding domain (RBD) corrected all transport defects and restored viability. Mutation of the RBD within this fragment caused lethality and perturbed binding to Ran guanosine triphosphate (GTP)-importin-β, accumulation of importin-β at nuclear pores, and cNLS-mediated protein import. These data suggest that a critical function of RanBP2 is to capture recycling RanGTP-importin-β complexes at cytoplasmic fibrils to allow for adequate cNLS-mediated cargo import.

Pleural dissemination of esophageal gastrointestinal stromal tumors after an eight-year interval following the primary surgery

A 71-year-old man who had undergone surgical resection of esophageal gastrointestinal stromal tumors (GISTs) through a right posterolateral thoracotomy 8 years earlier was referred for treatment of an anterior mediastinal mass discovered on a follow-up chest radiograph in October 2007. Computed tomography findings revealed a tumor, 82 x 49 mm, with calcification, in the anterior mediastinum. When we radically resected the tumor via a median sternectomy, we found that it was actually located in the pleural cavity, and there was a small nodule near the main tumor on other pleura. Microscopically, the tumor was comprised of uniform spindle cells with fibrillary eosinophilic cytoplasm. In addition, immunostaining showed that the tumor was positive for CD117 (c-kit). The diagnosis was pleural dissemination of esophageal GISTs 8 years after primary surgery, making this the first report of pleural dissemination of esophageal GISTs after such a prolonged postsurgical interval.

An allosteric mechanism to displace nuclear export cargo from CRM1 and RanGTP by RanBP1

The karyopherin CRM1 mediates nuclear export of proteins and ribonucleoproteins bearing a leucine-rich nuclear export signal (NES). To elucidate the precise mechanism by which NES-cargos are dissociated from CRM1 in the cytoplasm, which is important for transport directionality, we determined a 2.0-A resolution crystal structure of yeast CRM1:RanBP1:RanGTP complex, an intermediate in the disassembly of the CRM1 nuclear export complex. The structure shows that on association of Ran-binding domain (RanBD) of RanBP1 with CRM1:NES-cargo:RanGTP complex, RanBD and the C-terminal acidic tail of Ran induce a large movement of the intra-HEAT9 loop of CRM1. The loop moves to the CRM1 inner surface immediately behind the NES-binding site and causes conformational rearrangements in HEAT repeats 11 and 12 so that the hydrophobic NES-binding cleft on the CRM1 outer surface closes, squeezing out the NES-cargo. This allosteric mechanism accelerates dissociation of NES by over two orders of magnitude. Structure-based mutagenesis indicated that the HEAT9 loop also functions as an allosteric autoinhibitor to stabilize CRM1 in a conformation that is unable to bind NES-cargo in the absence of RanGTP.

Primary vaginal fibroleiomyosarcoma in a 4-year-old Holstein-Friesian cow

A case of fibroleiomyosarcoma of the vagina in a 4-year-old Holstein-Friesian cow is described. The tumour was 6.5 × 5 × 4.2 cm in size, weighed 87.73 g, and had a solid appearance. Histologically, the tumour was composed of smooth muscle and fibrous tissue components with spindle-shaped cells with eosinophilic fibrillary cytoplasm. Immunohistochemically, the tumour cells reacted with antibodies to \alpha-SMA, desmin, and vimentin but not with antibodies to CD34, CD68, and S-100 protein. Both histologically and immunohistochemically it showed the features of a fibroleiomyosarcoma.

Effort bruising disclosing Gaucher disease in a 55‐year‐old non‐Jewish woman

A 55-year-old previously healthy non-Jewish caucasian woman, working as a psychiatrist, presented with a several-months-long history of general weakness. The pastmedical history revealed effort bruising (Fig. 1) after harder physical work or intensive training from the age of 12 years, and periodic bilateral knee pain from the age of 15. The family history was not contributory. Full blood count showed Hb 114 g/L, WBC 3.27 10/L and platelet count 69 10/L. Laboratory investigations revealed normal liver function tests and APTT, but pathological values were observed for INR (1.3; normal range 0.9–1.2) and ferritin (817 mg/L; normal range 20–300). Neither hepatosplenomegaly nor lymphadenopathy was detected on physical examination, but further computed tomography (CT) imaging revealed slightly enlarged spleen (13.58 7.95 cm) without focal lesions (Fig. 2). Chronic ITP (idiopathic thrombocytopenic purpura) or other haematological disorder (e.g. lymphoma, myelodysplastic syndrome) was suspected, and bone marrow examination was performed, disclosing the presence of large cells with slightly basophilic, fibrillary cytoplasm (Fcrumpled tissue paper_ appearance) and eccentrically placed nuclei. These cells were identified as Gaucher cells (Figs. 3 and 4). The diagnosis of Gaucher disease (GD) was confirmed by a low activity of glucocerebrosidase in peripheral blood leukocytes (0.02 mkat/kg protein; normal range 0.2–0.7) and increased activity of plasma chitotriosidase (3260 mmol/h per L; normal range 9–244). Further direct DNA sequencing disclosed the mutation c.1226A>G (N370S) in the GBA1 gene. DNA sequencing suggested that the patient is probably homozygous for c.1226A>G, but hemizygosity with deletion in the second allele cannot be excluded. Once the diagnosis of GD was confirmed, additional work-up was conducted to establish possible additional reasons for bruising, other than thrombocytopenia. Serum protein electrophoresis and immunofixation test showed polyclonal IgM hyperglobulinaemia (3.84 g/L; normal range 0.3–2.8) without any further immunoglobulin abnormalities. Coagulation work-up revealed only border value of P-Factor XI (60%; normal range 60–140%), minimally decreased P-Factor XIII (69%; normal range 70–140%). P-Factor IX:C (0.77 kIE/L; normal values 0.45–1.90) and all other coagulation factors were within the normal limits. No platelet aggregation defects were detected. The patient did not use any antiplatelet (e.g. acetylsalicylic acid) or anticoagulant (e.g. warfarin) drugs. She was taking ascorbic acid and tranexamic acid daily in order to minimize the extent of bruising. Gaucher disease type I (GD I) can be found in all ethnic groups, but it is particularly prevalent among Ashkenazi Jews. In the general population GD I is J Inherit Metab Dis (2009) 32:758–761 DOI 10.1007/s10545-009-1217-6

Differentiated rhabdomyomatous tumors after chemotherapy for metastatic testicular germ-cell tumors: a clinicopathological study of seven cases mandating separation from rhabdomyosarcoma

To gain insight concerning prognosis, we investigated seven cases of post-chemotherapy retroperitoneal lymph-node dissections from patients with testicular germ-cell tumors that contained sizable nodules of differentiated skeletal muscle, but that lacked both a primitive cellular component and mitotic activity. The patients were 18–28 years old at the time of retroperitoneal lymph-node dissection. All had a previous non-seminomatous germ-cell tumor of the testis, five of which had a teratoma component. In one the testicular tumor had foci of embryonal rhabdomyosarcoma. The retroperitoneal lymph-node dissections were performed 0.2–4.7 years after orchiectomy, all following cisplatin-based chemotherapy, and contained rhabdomyomatous tumors that ranged from 0.8–5 cm. These consisted of nodular to diffuse aggregates of fetal-type rhabdomyocytes with central to peripheral nuclei and abundant, eosinophilic, fibrillary cytoplasm with occasional cross striations. Elongated myotubes with multiple nuclei in a common sarcoplasm occurred at least focally in all cases. Mild to moderate nuclear atypia, including nuclear enlargement and nucleolar prominence, was present, but mitotic activity, necrosis, and a primitive cellular component were absent. All but one retroperitoneal lymph-node dissection also contained other teratomatous elements. Follow-up in six patients showed three were disease free at 2.2–3.4 years; two developed recurrent teratoma at 1.3–3.7 years; and a sixth developed recurrent teratoma at 0.5 and 2 years, followed at 17 years by progressive tumor with elevated α-fetoprotein. No patient with available follow-up developed progressive sarcoma. We conclude that rhabdomyomatous tumors in retroperitoneal lymph-node dissection specimens after chemotherapy for metastatic testicular germ-cell tumors show clinical behavior similar to teratoma rather than rhabdomyosarcoma. We believe the most likely explanation for the finding of pure rhabdomyomatous tumors in this setting, a phenomenon sometimes termed ‘cytodifferentiation,‘ is selective persistence of differentiated tumor cells because of chemotherapy.

Sus1, Cdc31, and the Sac3 CID Region Form a Conserved Interaction Platform that Promotes Nuclear Pore Association and mRNA Export

SummaryThe yeast Sac3:Cdc31:Sus1:Thp1 (TREX-2) complex facilitates the repositioning and association of actively transcribing genes with nuclear pores (NPCs)—“gene gating”—that is central to integrating transcription, processing, and mRNA nuclear export. We present here the crystal structure of Sus1 and Cdc31 bound to a central region of Sac3 (the CID domain) that is crucial for its function. Sac3CID forms a long, gently undulating α helix around which one Cdc31 and two Sus1 chains are wrapped. Sus1 has an articulated helical hairpin fold that facilitates its wrapping around Sac3. In vivo studies using engineered mutations that selectively disrupted binding of individual chains to Sac3 indicated that Sus1 and Cdc31 function synergistically to promote NPC association of TREX-2 and mRNA nuclear export. These data indicate Sac3CID provides a scaffold within TREX-2 to integrate interactions between protein complexes to facilitate the coupling of transcription and mRNA export during gene expression.

The Cytologic Features of Sinonasal Undifferentiated Carcinoma and Olfactory Neuroblastoma

Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal tract. Olfactory neuroblastoma (ONB) is an uncommon neuroectodermal tumor of the superior nasal cavity. Upon examining these lesions, a broad differential diagnosis of poorly differentiated round cell tumors must be considered. The cytologic features of SNUC and ONB have been rarely reported. We searched our cytology files for cases of SNUC and ONB and assessed the following: cellularity, architecture, cytoplasm, cell size, nuclear contours, nucleoli, chromatin, anisonucleosis/anisocytosis, mitotic activity, background, and nuclear crush. Seven cases of SNUC produced hypercellular smears with a single-cell-predominant pattern. Cells were intermediate-sized with irregular nuclear contours and small nucleoli. Nuclear crush and mitotic figures were noted. The background exhibited naked nuclei and karyorrhectic debris. Of 7 cases, 6 (86%) exhibited vacuoles or extracellular lumina. The 10 cases of ONB exhibited cellularity, cellular arrangement, and chromatin similar to SNUC. In contrast, ONBs demonstrated fibrillary cytoplasm and smooth nuclear contours; mitotic figures were generally absent. Homer Wright rosettes were encountered in 9 cases (90%). We believe that in the appropriate clinical context, a specific cytologic diagnosis should be possible.