Invasive pseudomembranous upper airway and tracheal Aspergillosis refractory to systemic antifungal therapy and serial surgical debridement in an Immunocompetent patient.

BACKGROUND: The development of respiratory infections secondary to Aspergillus spp. spores found ubiquitously in the ambient environment is uncommon in immunocompetent patients. Previous reports of invasive upper airway aspergillosis in immunocompetent patients have generally demonstrated the efficacy of treatment regimens utilizing antifungal agents in combination with periodic endoscopic debridement, with symptoms typically resolving within months of initiating therapy. CASE PRESENTATION: A 43-year-old previously healthy female presented with worsening respiratory symptoms after failing to respond to long-term antibiotic treatment of bacterial sinusitis. Biopsy of her nasopharynx and trachea revealed extensive fungal infiltration and Aspergillus fumigatus was isolated on tissue culture. Several months of oral voriconazole monotherapy failed to resolve her symptoms and she underwent mechanical debridement for symptom control. Following transient improvement, her symptoms subsequently returned and failed to fully resolve in spite of increased voriconazole dosing and multiple additional tissue debridements over the course of many years. CONCLUSIONS: Invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients. In the rare instances that such infections do occur, combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach. However, some patients may continue to experience refractory symptoms. In such cases, continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved.

Contemporary diagnostics: sarcoma pathology update.

Sarcoma diagnosis continues to evolve as new information is discovered. Certain tumors have been downgraded (dermal leiomyosarcoma) and an atypical category designed for others. Recently entities include myxoinflammatory fibroblastic sarcoma, myoepithelioma, and pseudomyogenic hemangioendothelioma. The terms malignant fibrous histiocytoma and hemangiopericytoma are outdated. New immunostains (STAT6, SOX10, ERG) add diagnostic specificity, and new risk assessment models are described for sarcomas where grading and staging has failed to provide adequate prognosis.

PAX-8 expression in cutaneous ciliated cysts: evidence for Müllerian origin.

Cutaneous ciliated cysts (CCC) are exquisitely rare, benign cystic lesions demonstrating simple, ciliated epithelial linings reminiscent of fallopian tube epithelium. Most commonly, CCC show a predilection for the lower extremities of young reproductive age women and demonstrate immunohistochemical positivity for estrogen and progesterone receptors, supporting the theory that they are derived from ectopic Müllerian rests. PAX-8 is a paired box gene, important in the development of Müllerian and thyroid organs and has utility in the identification of tumors of Müllerian, renal, and thyroid origin. Prompted by the precedent studies on PAX-8 immunohistochemical expression in tumors of Müllerian origin, this article aimed to explore the utility of this antibody in defining the histogenesis of 2 bona fide cases of CCC, both occurring in young reproductive age women. Herein, 2 prototypic index cases of CCC with strong nuclear positivity for estrogen and progesterone receptors are shown to also have positive nuclear staining for PAX-8, further supporting their likely Müllerian origin. These data support the designation of these lesions as cutaneous Müllerian cysts, distinct from potential ciliated cysts of eccrine origin.

Clinical Presentation, Risk Factors, and Comparison of Laboratory Diagnostics for Seasonal Influenza Virus Among Cambodians From 2007 to 2020.

Background: Despite its global significance, challenges associated with understanding the epidemiology and accurately detecting, measuring, and characterizing the true burden of seasonal influenza remain in many resource-poor settings. Methods: A prospective observational study was conducted in Cambodia at 28 health facilities between 2007 and 2020 utilizing passive surveillance data of patients presenting with acute undifferentiated febrile illness (AUFI) to describe the prevalence of influenza A and B and characterize associated risk factors and symptoms using a questionnaire. A comparison of rapid influenza diagnostic tests (RIDTs) and real-time reverse transcription polymerase chain reaction (rRT-PCR) results was also conducted. Results: Of 30 586 total participants, 5634 (18.4%) tested positive for either influenza A or B, with 3557 (11.6%) positive for influenza A and 2288 (7.5%) positive for influenza B during the study. Influenza A and B were strongly associated with the rainy season (odds ratio [OR], 2.30; P < .001) and being from an urban area (OR, 1.45; P < .001). Analysis of individual symptoms identified cough (OR, 2.8; P < .001), chills (OR, 1.4; P < .001), and sore throat (OR, 1.4; P < .001) as having the strongest positive associations with influenza among patients with AUFI. Analysis comparing RIDTs and rRT-PCR calculated the overall sensitivity of rapid tests to be 0.492 (95% CI, 0.479-0.505) and specificity to be 0.993 (95% CI, 0.992-0.994) for both influenza type A and B. Conclusions: Findings from this 14-year study include describing the epidemiology of seasonal influenza over a prolonged time period and identifying key risk factors and clinical symptoms associated with infection; we also demonstrate the poor sensitivity of RIDTs in Cambodia.

Etiology and risk factors for diarrheal disease amongst rural and peri-urban populations in Cambodia, 2012-2018.

Diarrheal diseases are a leading cause of mortality and morbidity, disproportionally affecting persons residing in low and middle-income countries. Accessing high-resolution surveillance data to understand community-level etiology and risk remains challenging, particularly in remote and resource limited populations. A multi-year prospective cohort study was conducted in two rural and two peri-urban villages in Cambodia from 2012 to 2018 to describe the epidemiology and etiology of acute diarrheal diseases within the population. Suspected diarrheal episodes among participants were self-reported or detected via routine weekly household visits. Fresh stool and fecal swabs were tested, and acute-illness and follow-up participant questionnaires collected. Of 5027 enrolled participants, 1450 (28.8%) reported at least one diarrheal incident. A total of 4266 individual diarrhea case events were recorded. Diarrhea incidence rate was calculated to be 281.5 persons per 1000 population per year, with an event rate of 664.3 individual diarrhea events occurring per 1000 population per year. Pathogenic Escherichia coli, Aeromonas spp., and Plesiomonas shigelloides were the most prevalent bacterial infections identified. Hookworm and Strongyloides stercoralis were the predominant helminth species, while Blastocystis hominis and Giardia lamblia were the predominant protozoan species found. Norovirus genotype 2 was the predominant virus identified. Mixed infections of two or more pathogens were detected in 36.2% of positive cases. Risk analyses identified unemployed status increased diarrhea risk by 63% (HR = 1.63 [95% CI 1.46, 1.83]). Individuals without access to protected water sources or sanitation facilities were 59% (HR = 1.59 [95% CI 1.49, 1.69]) and 19% (HR = 1.19 [95% CI 1.12, 1.28]) greater risk of contracting diarrhea, respectively. Patient-level surveillance data captured in this long-term study has generated a unique spatiotemporal profile of diarrheal disease in Cambodia. Understanding etiologies, together with associated epidemiological and community-level risk, provides valuable public health insight to support effective planning and delivery of appropriate local population-targeted interventions.

Neurofibroma of the cervix presenting as cervical stenosis in a patient with neurofibromatosis type 1: a case report.

Neurofibromatosis type 1 is an autosomal dominant disorder characterized by the presence of cutaneous and subcutaneous neurofibromas as well as deep-seated plexiform neurofibromas. Although unusual, these lesions have been described in the gynecologic tract, including the cervix; however, when arising in this location, they are commonly asymptomatic or present with lower abdominal pain. Cervical neurofibromas presenting as cervical stenosis have not been described. Awareness by both the clinician and the pathologist of a patient's history is of great help when dealing with a specimen of a patient with neurofibromatosis type 1.

TERT gene rearrangement in chordomas and comparison to other TERT-rearranged solid tumors.

Chordomas are rare, slow-growing neoplasms thought to arise from the foetal notochord remnant. A limited number of studies that examined the mutational profiles in chordomas identified potential driver mutations, including duplication in the TBXT gene (encoding brachyury), mutations in the PI3K/AKT signaling pathway, and loss of the CDKN2A gene. Most chordomas remain without clear driver mutations, and no fusion genes have been identified thus far. We discovered a novel TERT in-frame fusion involving RPH3AL (exon 5) and TERT (exon 2) in the index chordoma case. We screened a discovery cohort of 18 additional chordoma cases for TERT gene rearrangement by FISH, in which TERT rearrangement was identified in one additional case. In our independent, validation cohort of 36 chordomas, no TERT rearrangement was observed by FISH. Immunohistochemistry optimized for nuclear TERT expression showed at least focal TERT expression in 40/55 (72.7%) chordomas. Selected cases underwent molecular genetic profiling, which showed low tumor mutational burdens (TMBs) without obvious driver oncogenic mutations. We next examined a cohort of 1,913 solid tumor patients for TERT rearrangements, and TERT fusions involving exon 2 were observed in 7/1,913 (0.4%) cases. The seven tumors comprised five glial tumors, and two poorly differentiated carcinomas. In contrast to chordomas, the other TERT-rearranged tumors were notable for higher TMBs, frequent TP53 mutations (6/7) and presence of other driver oncogenic mutations, including a concurrent fusion (TRIM24-MET). In conclusion, TERT gene rearrangements are seen in a small subset (2/55, 3.6%) of chordomas. In contrast to other TERT-rearranged tumors, where the TERT rearrangements are likely passenger events, the possibility that TERT protein overexpression representing a key event in chordoma tumorigenesis is left open.

Trisomy 21 enhances human fetal erythro-megakaryocytic development.

Children with Down syndrome exhibit 2 related hematopoietic diseases: transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (AMKL). Both exhibit clonal expansion of blasts with biphenotypic erythroid and megakaryocytic features and contain somatic GATA1 mutations. While altered GATA1 inhibits erythro-megakaryocytic development, less is known about how trisomy 21 impacts blood formation, particularly in the human fetus where TMD and AMKL originate. We used in vitro and mouse transplantation assays to study hematopoiesis in trisomy 21 fetal livers with normal GATA1 alleles. Remarkably, trisomy 21 progenitors exhibited enhanced production of erythroid and megakaryocytic cells that proliferated excessively. Our findings indicate that trisomy 21 itself is associated with cell-autonomous expansion of erythro-megakaryocytic progenitors. This may predispose to TMD and AMKL by increasing the pool of cells susceptible to malignant transformation through acquired mutations in GATA1 and other cooperating genes.

Case report: hemosiderotic fibrohistiocytic lipomatous lesion: a clinicopathologic characterization.

BACKGROUND: A hemosiderotic fibrohistiocytic lipomatous lesion, also called hemosiderotic fibrolipomatous tumor, is a rare and recently described fibrolipomatous entity. Initially considered the result of a reactive inflammatory process from trauma or vascular disease, newer evidence suggests it may be neoplastic in origin. CASE REPORT: We report the case of a 56-year-old woman with a painful mass in the dorsal aspect of the foot diagnosed as a hemosiderotic fibrohistiocytic lipomatous lesion. LITERATURE REVIEW: We reviewed all 31 published cases of hemosiderotic fibrohistiocytic lipomatous lesions looking for common clinical, imaging, and histologic patterns. Hemosiderotic fibrohistiocytic lipomatous lesions occur predominantly in the fifth and sixth decades of life (average age, 49.5 years; range, 0.67-74 years). Females predominate 22 to 9. Thirteen of 28 patients had histories of trauma or vasculopathy. Twenty-six of 31 lesions were in the foot. The MRI signal of a hemosiderotic fibrohistiocytic lipomatous lesion follows fat in all sequences. Stranding or septations also frequently are seen. Histologically, the lesions are composed of three main elements in varying proportions: mature adipocytes, spindle cells, and hemosiderin pigment. Ten of 27 resected lesions recurred. Resection types are not reported in many cases. Four of 15 lesions recurred after marginal/intralesional excision, whereas none of three lesions treated by wide excision recurred. PURPOSE AND CLINICAL RELEVANCE: The high recurrence rate may be related to the difficulty in determining intraoperatively that a resection is complete, secondary to the lack of anatomic boundaries such as a pseudocapsule. Any attempt at wide resection must weigh the morbidity of this surgery against that of a recurrence after a resection which seemed complete intraoperatively. There have been no reports of metastasis.

Primary Pulmonary Myxoid Sarcoma and Myxoid Angiomatoid Fibrous Histiocytoma: A Unifying Continuum With Shared and Distinct Features.

Primary pulmonary myxoid sarcoma (PPMS) is a recently reported, exceedingly rare low-grade lung neoplasm characterized by reticular/lace-like growth of spindle to epithelioid cells embedded in an abundant myxoid matrix. Morphologically, it overlaps with a myxoid variant of angiomatoid fibrous histiocytoma (AFH) of the soft tissue. Genetically, they were both reported to harbor EWSR1-CREB1 fusion, while EWSR1-ATF1 has only been reported in AFH thus far. We report a case of primary pulmonary low-grade myxoid spindle cell tumor with morphologic and immunohistochemical features of PPMS but with an EWSR1-ATF1 fusion gene. In addition, we also encountered a case of endobronchial AFH with EWSR1-CREB1 translocation but also focal morphologic features of PPMS. These findings provide new evidence supporting the concept that PPMS and a myxoid variant of AFH represent a continuum with overlapping histologic, immunohistochemical, and genetic features.

Combined Sclerosing and Spindle Cell Rhabdomyosarcoma in Previous Craniotomy Site: A Case Report and a Review of the Literature.

Sclerosing rhabdomyosarcoma (RMS) is a rare subtype of RMS with unique prominent stromal hyalinization and a pseudovascular architecture. It overlaps morphologically with spindle cell RMS and poses both diagnostic and therapeutic challenges because of its rarity and aggressive clinical course. In this article, we report a case of sclerosing RMS arising from a prior craniotomy site, which demonstrated both sclerosing and spindle cell components. A literature review of RMS with sclerosing morphology identified 122 cases. Our review documents the following: sclerosing RMS occurs in both childhood and adult populations, has a predilection for the head and neck areas, and has a worse prognosis in adults. Sclerosing RMS harbors a high frequency of MYOD1 mutations, conferring a poor clinical outcome. Sclerosing RMS and spindle RMS likely represent a morphologic spectrum of one entity.

PD-L1 Expression Reveals Significant Association With Squamous Differentiation in Upper Tract Urothelial Carcinoma.

OBJECTIVES: Limited literature is available on the tumor microenvironment (TM) of upper tract urothelial carcinoma (UTUC). This study comprehensively reviews programmed death 1 receptor (PD-1)-positive and CD8+ tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression on tumor epithelium (TE). METHODS: Seventy-two nephroureterectomy specimens were analyzed for PD-L1, PD-1, and CD8. One percent or more tumor and lymphohistiocyte PD-L1 expression was considered positive. TIL density by H&E was scored semiquantitatively from 0 to 3, and CD8+ and PD-1+ TILs were quantified in hotspots. RESULTS: Of the cases, 37.5% demonstrated PD-L1+ on TE. PD-L1+ TE showed an association with pathologic stage (P = .01), squamous differentiation (SqD) (P < .001), TILs by H&E (P = .02), PD-1+ peritumoral TILs (P = .01), and PD-L1+ peritumoral lymphohistiocytes (P = .002). Finally, there was a significant difference in PD-1+ peritumoral TILs in cases with SqD vs no SqD (P = .03). CONCLUSIONS: Aggressive UTUC is associated with a distinct TM. Furthermore, TM of UTUC-SqD was distinctly different from those with no SqD, warranting study in a larger cohort.

Primary Cutaneous Angiosarcoma of the Eyelid: A Diagnostic and Therapeutic Challenge.

Primary cutaneous angiosarcoma is a rare vasoformative malignant neoplasm that can present a diagnostic and therapeutic challenge. We describe a 76-year-old Caucasian man with right upper eyelid swelling and nodularity, initially suspected clinically to represent either ocular adnexal lymphoma or basal cell carcinoma. Incisional biopsy and wide resection of the mass with frozen section control of margins were interpreted as compatible with hobnail (Dabska-retiform) hemangioendothelioma. Foci of atypia were noted in the tumor, raising speculation of evolution into a more aggressive neoplasm, such as conventional angiosarcoma. The patient subsequently underwent two additional wide resections with frozen section control of margins in an attempt to obtain complete excision of residual tumor, which demonstrated histopathologic features favoring angiosarcoma. The histologic material from the original and subsequent resections was sent in consultation to several soft tissue pathology experts and the final diagnosis of low-grade cutaneous angiosarcoma was established. Despite repeated surgical interventions, there was continued persistence of the tumor in the deep orbital tissues. Various management options, including adjuvant radiotherapy/chemotherapy with and without orbital exenteration, were discussed. The patient decided against further surgical intervention and is currently undergoing adjuvant radiotherapy/chemotherapy. This case illustrates the diagnostic and management difficulties of ocular adnexal angiosarcoma.

Leiomyosarcoma of the head and neck: A 17-year single institution experience and review of the National Cancer Data Base.

BACKGROUND: Leiomyosarcoma is a rare neoplasm of the head and neck. The purpose of this study was to present our single-institution case series of head and neck leiomyosarcoma and a review of cases in the National Cancer Data Base (NCDB). METHODS: Patients with head and neck leiomyosarcoma at the University of Pennsylvania and in the NCDB were identified. Demographic characteristics, tumor factors, treatment paradigms, and outcomes were evaluated for prognostic significance. RESULTS: Nine patients with head and neck leiomyosarcoma from the institution were identified; a majority had high-grade disease and cutaneous leiomyosarcoma, with a 5-year survival rate of 50%. Two hundred fifty-nine patients with leiomyosarcoma were found in the NCDB; macroscopic positive margins and high-grade disease were associated with poor prognosis (P < .01), and positive surgical margins were related to adjuvant radiation (P < .001). CONCLUSION: Head and neck leiomyosarcoma presents at a high grade and is preferentially treated with surgery. Several demographic and tumor-specific factors are associated with outcomes and prognosis.

Metastatic Alveolar Soft Part Sarcoma of the Spinal Cord: A Case Report and Review of Literature.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare, malignant soft-tissue neoplasm typically seen in young adults that possesses an unusual tendency to metastasize. Metastases to the intramedullary compartment of the spinal cord, however, are exceptionally rare and have not been described in the literature. CASE DESCRIPTION: We report the case of a 23-year-old woman with disseminated ASPS to the lung and brain who presented with progressive lower-extremity weakness and loss of sensation after radiation and chemotherapy. Magnetic resonance imaging revealed a 1.3-cm avidly enhancing lesion within the central thoracic spinal cord at T3. A T2-T4 laminectomy was undertaken and resulted in a gross total resection. Histopathologically, the mass was composed of organoid nests containing epithelioid cells with eosinophilic, granular cytoplasm separated by sinusoidal spaces. Immunohistochemistry demonstrated convincing positive TFE3 staining. Postoperative imaging confirmed the complete resection of the mass, and her examination was notable for intact sensation and impaired motor function that gradually improved. CONCLUSIONS: A review of the literature found that the reported case represents the first instance of primary or metastatic ASPS in the spinal cord. Metastatic ASPS should thus be included in the differential diagnosis in patients with known disease and neurologic impairment or back pain. Imaging of the spine should then be considered.

Prognostic significance of MCM2, Ki-67 and gelsolin in non-small cell lung cancer.

BACKGROUND: Uncontrolled proliferation and increased motility are hallmarks of neoplastic cells, therefore markers of proliferation and motility may be valuable in assessing tumor progression and prognosis. MCM2 is a member of the minichromosome maintenance (MCM) protein family. It plays critical roles in the initiation of DNA replication and in replication fork movement, and is intimately related to cell proliferation. Ki-67 is a proliferation antigen that is expressed during all but G0 phases of the cell cycle. Gelsolin is an actin-binding protein that regulates the integrity of the actin cytoskeletal structure and facilitates cell motility. In this study, we assessed the prognostic significance of MCM2 and Ki-67, two markers of proliferation, and gelsolin, a marker of motility, in non-small cell lung cancer (NSCLC). METHODS: 128 patients with pathologically confirmed, resectable NSCLC (stage I-IIIA) were included. Immunohistochemistry was utilized to measure the expressions of these markers in formalin-fixed, paraffin-embedded tumor tissues. Staining and scoring of MCM2, Ki-67 and gelsolin was independently performed. Analyses were performed to evaluate the prognostic significance of single expression of each marker, as well as the prognostic significance of composite expressions of MCM2 and gelsolin. Cox regression and Kaplan-Meier survival analysis were used for statistical analysis. RESULTS: Of the three markers, higher levels of gelsolin were significantly associated with an increased risk of death (adjusted RR = 1.89, 95% CI = 1.17-3.05, p = 0.01), and higher levels of MCM2 were associated with a non-significant increased risk of death (adjusted RR = 1.36, 95% CI = 0.84-2.20, p = 0.22). Combined, adjusted analyses revealed a significantly poor prognostic effect for higher expression of MCM2 and gelsolin compared to low expression of both biomarkers (RR = 2.32, 95% CI = 1.21-4.45, p = 0.01). Ki-67 did not display apparent prognostic effect in this study sample. CONCLUSION: The results suggest that higher tumor proliferation and motility may be important in the prognosis of NSCLC, and composite application of biomarkers might be of greater value than single marker application in assessing tumor prognosis.

Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients.

Synovial sarcomas are aggressive spindle cell sarcomas containing in some cases areas of epithelial differentiation. They consistently show a specific t(X;18;p11;q11), which usually represents either of two gene fusions, SYT-SSX1 or SYT-SSX2, encoding putative transcriptional proteins differing at 13 amino acid positions. Previous studies have suggested that patients with SYT-SSX2 tumors do better than those with SYT-SSX1 tumors, but the study groups were too limited to be conclusive. To address this issue more definitively, we collected data on SYT-SSX fusion type, pathology, and clinical course in a retrospective multi-institutional study of 243 patients (age range, 6-82) with synovial sarcoma. SYT-SSX1 and SYT-SSX2 fusions were detected in 147 tumors (61%) and 91 tumors (37%), respectively. Histologically, 61 (25%) were classified as biphasic type and 180 (74%) as monophasic type based on the presence or absence of areas of glandular epithelial differentiation, respectively. Median and 5-year overall survivals for the SYT-SSX1 and SYT-SSX2 groups were 6.1 years and 53%, and 13.7 years and 73%, respectively. Overall survival was significantly better among SYT-SSX2 cases (P = 0.03), among cases localized at diagnosis (P < 0.0001), and among patients with primary tumors < 5 cm in greatest dimension (P = 0.01). Age, sex, histological type, and axial versus peripheral primary site had no impact on overall survival. The impact of fusion type on survival remained significant when stratified for primary tumor size (P = 0.03) but was no longer significant when stratified for disease status at presentation. This may reflect the tendency for patients with SYT-SSX1 tumors to present more often with metastatic disease (P = 0.05). Cox regression identified disease status (P < 0.0001) and primary tumor size (P = 0.04) as the only factors independently predictive of overall survival in the subset of 160 patients with information on all of the factors. Within the subset of patients with localized disease at diagnosis (n = 202), the median and 5-year survival for the SYT-SSX1 and the SYT-SSX2 groups were 9.2 years and 61% versus 13.7 years and 77%, respectively. Patients whose tumors contained the SYT-SSX2 fusion (P = 0.08) or were smaller (P = 0.12) showed a trend toward better survival by log-rank test, whereas tumor histology had no impact (P = 0.8). In a Cox regression analysis considering all of the factors, SYT-SSX fusion type emerged as the only independent significant factor (P = 0.04) for overall survival within the subset of 133 patients with localized disease at diagnosis who had information on all of the factors. Among other comparisons, there was a strong association of fusion type and morphology (P < 0.001), with almost all of the SYT-SSX2 tumors showing absence of glandular differentiation (monophasic histology) and almost all of the biphasic tumors containing SYT-SSX1. There was also a statistically significant association of fusion type and patient sex (P = 0.03); specifically, the male:female ratio of SYT-SSX1 cases was 1:1, whereas for SYT-SSX2 cases, it was close to 1:2. Overall, SYT-SSX fusion type appears to be the single most significant prognostic factor by multivariate analysis in patients with localized disease at diagnosis. SYT-SSX fusion type also appears to exert part of its impact on prognosis before presentation through its association with stage at diagnosis. In addition, the associations of SYT-SSX fusion type with patient sex and tumor epithelial differentiation point to interesting mechanistic biological differences.

Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR.

A highly distinctive subset of renal neoplasms of children and young adults contains a t(6;11)(p21;q12), a translocation recently been shown to result in fusion of Alpha, a gene on 11q12, with the transcription factor gene TFEB on 6p21. To define the clinicopathologic spectrum of this nascent entity and to establish immunohistochemical (IHC) and molecular methods for the detection of the specific Alpha-TFEB fusion, we studied 7 renal neoplasms that showed the t(6;11) by cytogenetic or molecular analysis (patient age: range, 9-33 years; mean, 17 years). While all tumors were confined to the kidney, 3 tumors demonstrated vascular invasion. In limited follow-up, none has metastasized. We postulated that the Alpha-TFEB gene fusion may result in deregulated expression of TFEB protein that would be detectable by IHC. Using a polyclonal antibody to TFEB on formalin-fixed, paraffin-embedded tissue sections, we found that all 7 renal neoplasms with the t(6;11) demonstrated moderate (2 cases) or strong (5 cases) nuclear TFEB immunoreactivity. In contrast, none of 1089 other tumors (of 74 histologic types from 16 sites) labeled significantly for TFEB. Nuclear immunoreactivity for TFEB in normal tissues was extremely rare, limited to weak labeling of scattered benign lymphocytes. We also show that the Alpha-TFEB fusion RNAs are highly variable in size and structure, making detection by reverse-transcriptase polymerase chain reaction (RT-PCR) less reliable than for other gene fusions. Because Alpha is an intronless gene and therefore lacks splice signals, we hypothesized that DNA PCR and RT-PCR products would be identical, allowing for the use of more robust molecular assays based on genomic DNA. Indeed, in 2 cases with available frozen tissue, we showed the genomic Alpha-TFEB junction detected by DNA PCR to be identical to the Alpha-TFEB fusion mRNA detected by RT-PCR. In summary, renal neoplasms with the t(6;11) are a distinctive neoplastic entity with many similarities to the Xp11 translocation carcinomas, and together with the latter form a growing "MiTF/TFE family" of translocation carcinomas. Nuclear immunoreactivity for TFEB protein is a highly sensitive and specific diagnostic marker for these renal neoplasms. Finally, the special molecular features of the Alpha-TFEB gene fusion allow its molecular detection by DNA PCR as a robust alternative to RT-PCR in clinical tumor samples.

Endoscopic resection of a venous hemangioma of the optic nerve sheath.

We describe a case of a venous hemangioma that arose in the optic nerve sheath of the orbital apex in a 28-year-old man who presented with progressive vision loss. To the best of our knowledge, this is the first reported case of a venous hemangioma occurring at this location. A definitive diagnosis and partial excision was achieved via an endoscopic transsphenoethmoid approach with interactive, computer-assisted, frameless stereotactic surgical navigation. The intervention resulted in minimal morbidity, demonstrating yet again that this surgical approach is a safe and effective way to treat lesions of the orbital apex.