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Object The use of endoscopic endonasal surgery (EES) for skull base pathologies in the pediatric population presents unique challenges and has not been well described. The authors reviewed their experience with endoscopic endonasal approaches in pediatric skull base surgery to assess surgical outcomes and complications in the context of presenting patient demographics and pathologies. Methods A retrospective review of 133 pediatric patients who underwent EES at our institution from July 1999 to May 2011 was performed. Results A total of 171 EESs were performed for skull base tumors in 112 patients and bony lesions in 21. Eighty-five patients (63.9%) were male, and the mean age at the time of surgery was 12.7 years (range 2.3–18.0 years). Skull base tumors included angiofibromas (n = 24), craniopharyngiomas (n = 16), Rathke cleft cysts (n = 12), pituitary adenomas (n = 11), chordomas/chondrosarcomas (n = 10), dermoid/epidermoid tumors (n = 9), and 30 other pathologies. In total, 19 tumors were malignant (17.0%). Among patients with follow-up data, gross-total resection was achieved in 16 cases of angiofibromas (76.2%), 9 of craniopharyngiomas (56.2%), 8 of Rathke cleft cysts (72.7%), 7 of pituitary adenomas (70%), 5 of chordomas/chondrosarcomas (50%), 6 of dermoid/epidermoid tumors (85.7%), and 9 cases of other pathologies (31%). Fourteen patients received adjuvant radiotherapy, and 5 received chemotherapy. Sixteen patients (15.4%) showed tumor recurrence and underwent reoperation. Bony abnormalities included skull base defects (n = 12), basilar invagination (n = 4), optic nerve compression (n = 3) and trauma (n = 2); preexisting neurological dysfunction resolved in 12 patients (57.1%), improved in 7 (33.3%), and remained unchanged in 2 (9.5%). Overall, complications included CSF leak in 14 cases (10.5%), meningitis in 5 (3.8%), transient diabetes insipidus in 8 patients (6.0%), and permanent diabetes insipidus in 12 (9.0%). Five patients (3.8%) had transient and 3 (2.3%) had permanent cranial nerve palsies. The mean follow-up time was 22.7 months (range 1–122 months); 5 patients were lost to follow-up. Conclusions Endoscopic endonasal surgery has proved to be a safe and feasible approach for the management of a variety of pediatric skull base pathologies. When appropriately indicated, EES may achieve optimal outcomes in the pediatric population.

CONTEXT: Tuberous sclerosis complex (TSC) is a genetic disease in the group known as neurocutaneous syndromes, with dominant autosomal inheritance. It is characterized by skin and adnexal lesions and central and peripheral nervous system tumors, with neurological and psychiatric findings. It may affect the heart, kidneys, eyes, face, bones, lungs, stomach and dentition. CASE REPORT: We present the case of a 66-year-old man with dermatological signs that included hypopigmented maculae, confetti-like lesions, shagreen plaque, angiofibromas on nasolabial folds, neck and back, nail dystrophy and periungual fibromas on fingers and toes. An electroencephalogram produced normal results, but magnetic resonance imaging showed a nodular image measuring 1.2 x 1.0 cm close to the Monro foramen, which was similar to cerebral parenchyma and compatible with a subependymal giant-cell astrocytoma. A conservative approach was taken, through control imaging examinations on the lesion for seven years, with absence of any expansive process or neurological symptoms. Abdominal ultrasonography revealed a solid, heterogenic and echogenic mass with a calcified focus, measuring 4.6 x 3.4 cm, in the rightkidney, compatible with angiomyolipoma. The patient was treated by means of complete nephrectomy because of malignant areas seen on histopathological examination and died one month after the procedure. This case report illustrates the importance of oral clinical findings such as dental enamel pits and angiofibromas in making an early diagnosis of TSC, with subsequent screening examinations, treatment and genetic counseling.

Tuberous sclerosis complex (TSC) is a dominantly inherited disorder which is characterized by hamartomas seen in the whole body. Angiofibromas of the face are often described, and there are various symptoms in various organs such as brain, lung, heart, kidney and bone. Oral manifestations include enamel hypoplasia, gingival fibromas and mandibular cysts. We have experienced a case of sclerosing fibroma of the chin removed surgically in a 2-year girl with tuberous sclerosis complex. Ten-year after the surgery we found a local recurrence of the tumor with emerging of other characteristic symptoms of the disease complex.

Angiofibromas are rare vascular tumors which originate predominantly in the nasopharynx and occur typically in male adolescents. Extranasopharyngeal sites such as nasal cavity and paranasal sinuses are less frequent. This review article was undertaken to evaluate the incidence, clinical features and management of extranasopharyngeal angiofibromas originating exclusivelly from nasal cavity structures. Our focus of interest was to evaluate the significance of immunohistochemical analysis in diagnosis of such extremely rare neoplasms. In the PubMed and Google Search, we found only 39 cases of nasal angifibroma, 27 males and 12 females from 1980 to 2012. The most prevalent site of origin was nasal septum, followed by inferior and middle turbinate. The commonest symptoms were nasal obstruction and epistaxis. Nasal angiofibromas are clinically distinct from nasopharyneal angiofibromas and can therefore be misdiagnosed. The differential diagnosis includes other vascular lesions, such as lobular capillary hemangioma and sinonasal-type hemangiopericytoma. Although immunohistochemistry is not necessary for differentiation between angiofibroma and capillary hemangioma, that diagnostic procedure may be helpful in distinction from sinonasal hemangiopericytoma. As an ilustration for immunohistochemical analysis, we presented a case of an elderly woman with tumor arising from the middle turbinate, diagnosed as angiofibroma. The staining was positive for CD34, CD31, factor VIII, vimentin and smooth muscle α-actin, and negative for desmin.

Vascular tumors are distinguished from vascular malformations by the presence of mitosis, or increased endothelial turnover. Vascular tumors can be benign, locally aggressive, or malignant. Infantile hemangiomas, the most prevalent vascular tumor, are largely benign entities, but can be functionally and cosmetically impairing if not treated in a timely manner. This chapter addresses infantile hemangiomas, vascular tumors with serious consequences (Kasabach-Merritt phenomenon and multifocal lymphangioendotheliomatosis with thrombocytopenia), and common benign tumors (pyogenic granulomas and angiofibromas).

Microcystic lymphatic malformations (MLM) are low-flow vascular malformations composed of multiple small cysts. MLM usually affect deep-lying structures, which makes their treatment even more difficult and complex. A novel and interesting treatment is rapamycin, a mammalian target of rapamycin inhibitor that when orally administrated has offered favorable results. However, until recently, topical rapamycin had not been used in the treatment of MLM. Case 1 is a girl aged 13 years with extensive MLM affecting the muscles in the right buttock. The patient had received frequent cycles of cryotherapy, but they had failed to control the associated symptoms. In the previous 12 months, the patient had reported greater discomfort, swelling, exudate, and superinfection of the affected region. Because no specific treatment has yet been approved for MLM, and as a step before the use of aggressive systemic or intralesional treatments, it was decided to initiate treatment with 1% rapamycin ointment. After 4 months of treatment, the patient presented a marked improvement, with a significant reduction of associated complications and no major side effects. Case 2 is a boy aged 5 years who underwent surgery for an intergluteal lipoblastoma at 3 weeks of life and developed a MLM on the scar 6 months afterward. The lesion showed slow growth and continuous exudation with frequent episodes of superinfection. Treatments with laser multiplex and intralesional bleomycin were performed unsuccessfully. In the previous 4 months, the patient had been treated with 1% rapamycin ointment with significant improvement and no side effects.

Angiofibromas are one of the dermatological hallmarks of tuberous sclerosis. Various ablative treatments have been trialled and more recently topical rapamycin has been proposed. We present our experience of treatment of angiofibromas using carbon dioxide (CO2) laser ablation and provide a timely literature review. Nine patients were retrospectively identified as being treated with CO2 laser between 2009 and 2015. Three patients were male, six were female, median age at first treatment was 28 (range 15–49) years and the median number of treatments was two (range 1–17). Four of these patients could be contacted for a post-treatment telephone interview. All reported an improvement in appearance of angiofibromas following treatment and that they would recommend CO2 laser ablation to others. Three of the four reported recurrence of some lesions following treatment. The only side effect reported by one patient was transient hyperpigmentation. CO2 laser ablation appears to be a well-tolerated, efficacious treat...

The greatest challenge in the surgical treatment of angiofibromas is dealing with the hypervascularity of these tumors. Staging systems that take into account the vascularity of the tumor may be more prognostic. A variety of treatment strategies are used to deal with the vascularity of angiofibromas, including preoperative embolization, segmentation of the tumor into vascular territories, use of hemostatic tools, and staging of surgery. Even large angiofibromas with intracranial extension and residual vascularity can be successfully managed by a skull base team using endoscopic techniques.

Angiofibromas are rare tumors of the head and neck that mostly occur in the sphenopalatine region. We present a case of angiofibroma in a young male patient with an unusual and extremely rare localization, which to our knowledge has not been described before. It was situated in the tentorium and spread to the supratentorial and infratentorial regions. The patient initially presented with symptoms of increased intracranial pressure. After a diagnostic evaluation was done, the whole tumor was successfully removed using the supratentorial and infratentorial approach and the microsurgical technique.

Objectives To compare the clinical utility of four juvenile nasal angiofibroma (JNA) staging systems in a large cohort of patients. Design Retrospective case series. Setting Tertiary referral academic center. Participants Pediatric patients undergoing surgical resection of JNAs between January 2008 and June 2015. Main Outcome Measures Intraoperative blood loss and transfusions, number of staged operations, postoperative residual disease, and recurrent disease. Results In total, 34 patients were identified; all underwent preoperative embolization followed by surgery. Of the 34 patients, 33 (97%) underwent an exclusively endoscopic surgical approach, with 6 (18%) requiring planned staged operations. Ten (29%) patients had residual disease and three (9%) required further surgical resection. Using the area under the curve (AUC) of receiver operating characteristic curves, the University of Pittsburgh Medical Center (UPMC) staging system was most predictive of patients who required staged procedures, received intraoperative transfusions, and had residual postoperative disease (AUC: 0.89, 0.88, 0.86, respectively). Conclusions The UPMC JNA staging system accounts for both route of skull base extension and tumor vascularity, which are two important tumor attributes in the age of preoperative embolization and endoscopic endonasal surgery. The UPMC staging system is a reliable modern staging system that closely reflects prognostic information and aids in surgical planning.

International audience; Medicines for the treatment of rare diseases frequently do not attract the interest of the pharmaceutical industry, and hospital pharmacists are thus often requested by physicians to prepare personalized medicines. Tuberous Sclerosis Complex (TSC) is a rare disease that causes disfiguring lesions named facial angiofibromas. Various topical formulations of rapamycin (=sirolimus) have been proved effective in treating these changes in small case series. The present study provides for the first time characterization of a 0.1% rapamycin cream formulation presenting good rapamycin solubilisation. The first step of the formulation is solubilisation of rapamycin in Transcutol®, and the second step is the incorporation of the mixture in an oil-in-water cream.A HPLC stability-indicating method was developed. Rapamycin concentration in the cream was tested by HPLC and confirmed that it remained above 95% of the initial concentration for at least 85 days, without characteristic degradation peaks. The preparation met European Pharmacopoeia microbial specifications throughout storage in aluminum tubes, including when patient use was simulated. Odour, appearance and colour of the preparation were assessed and no change was evidenced during storage. The rheological properties of the cream also remained stable throughout storage.To conclude, we report preparation of a novel cream formulation presenting satisfactory rapamycin solubilisation for the treatment of TSC cutaneous manifestations, with stability data. The cream is currently being used by our patients. Efficacy and tolerance will be reported later.

Objectives: Endoscopic resection has become an established surgical option for most juvenile nasopharyngeal angiofibromas (JNA). However, surgical management of JNA with intracranial extension remains challenging. This retrospective multicenter study reviews a series of patients with advanced stage JNA treated via endonasal/endoscopic approach. Methods: The experience of five academic tertiary or quaternary care ORL-HNS Departments were included. Medical records of all patients operated for JNA staged as Radkowski stage IIIA or IIIB were reviewed. Main outcome measures included intraoperative blood loss, length of hospital stay, complication rate, and rate of persistence or recurrence. Results: A total of 74 male patients with stages IIIA and IIIB were included. The mean age was 16.4 years and preoperative embolization was performed in 71 patients. The mean blood loss in 45 patients for whom the data was available was 1279.7 ml. The more anatomic subsites were involved, the higher the risk was of intraoperative bleeding. The mean follow-up for 54 out of 73 patients was 37.9 months. Patients with residual disease are significantly linked to involvement of combined (anterior-lateral and posterior) anatomic subsites and to a higher number of affected subsites. At last follow-up, all patients were asymptomatic and those with residual tissue displayed no imaging signs of growth. Conclusions: This retrospective multicenter study supports the notion that expanded endonasal endoscopic approaches for advance staged JNA are a feasible option associated with good long-term results.

Objectives/Hypothesis: To explore the molecular genetic background of juvenile nasopharyngeal angiofibromas and to identify biological processes and putative factors determining the different growth patterns of these tumors. Study Design: By comparing copy number and gene expression level changes of two clinically different phenotypes of juvenile nasopharyngeal angiofibromas, we aimed to find processes essential in the growth and development of these tumors. Based on the results and prior knowledge of the proteins significance for growth, we studied the expression of tyrosine kinase SYK in 27 tumor samples. Methods: Comparative genomic hybridization and gene expression analyses were performed for the two tumor samples, and protein expression of SYK was studied in 27 samples by immunohistochemical staining. Results: Between low- and high-stage juvenile nasopharyngeal angiofibromas, 1,245 genes showed at least a two-fold change in expression. The corresponding proteins of these transcripts were enriched in different biological processes. Protein kinase SYK was expressed in all 27 samples, and its intensity significantly correlated with tumor stage. Conclusions: Because the molecular genetic background of juvenile nasopharyngeal angiofibroma is unknown, our aim was to investigate genomic alterations that could associate to low- and high-stage tumors. We were able to identify gene expression changes that relate to particular biological processes, but assessing clinically relevant molecular profiles still requires further characterization. Due to the low incidence of juvenile angiofibroma, in the future a combination of molecular profiling data from several studies would be useful in understanding the molecular background of the disease. Laryngoscope, 2012

Tuberous sclerosis complex (TCS) is a genetic disorder with a variable clinical presentation. It is commonly characterized by seizures, mental retardation and cutaneous angiofibromas. Renal manifestations frequently include angiomyolipomas and cysts which lead to chronic kidney disease. We report a case of valproic acid-induced acute pancreatitis in a dialysis patient affected by TCS. The case demonstrates the importance of assessing antiepileptic drug treatment in dialysis patients. © 2012 Società Italiana di Nefrologia.

Background Juvenile nasopharyngeal angiofibromas (JNAs) with significant skull base involvement and intracranial extension are challenging tumors. We evaluated our experience in the treatment of extensive JNAs through resection followed by radiosurgery. Methods From 1999 to 2007, 10 advanced JNAs (Andrews grade IV) were treated by primary surgical resection followed by gamma knife radiosurgery of residual tumor. Tumor control and treatment morbidity were evaluated. Results Six months after radiosurgery and annually thereafter, an imaging study was done that revealed decrement in tumor size in 3 patients and no change in 7 patients, after a 3-year minimum follow-up. Clinically, patients are asymptomatic. Conclusion An efficient strategy in the management of extensive JNAs is the use of a multimodality approach, in which surgical resection is followed by the treatment with radiosurgery in critical locations. These therapeutic schemes are safe and offer long-term tumor control. © 2012 Wiley Periodicals, Inc. Head Neck, 2013

Background. Glucocorticoids (GCs) not only regulate metabolic and inflammatory mechanisms, but also are known to suppress tumor growth. Despite previous detection of glucocorticoid receptors (GRs) in juvenile angiofibromas, their distribution and function have not further been studied. Methods. Juvenile angiofibroma tissue (n ¼ 30), nasal mucosa specimens (n ¼ 10), subepithelial stroma of nasal mucosa (n ¼ 20), and primary fibroblasts from juvenile angiofibroma (n ¼ 6) and nasal mucosa samples (n ¼ 6) were analyzed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence staining. The antiproliferative effect of GCs (dexamethasone, prednisolone, and hydrocortisone) in vitro was assessed using a bromdeoxyuridine (BrdU) assay. Results. An upregulation of GR transcripts and protein was shown in juvenile angiofibroma tissue and primary mesenchymal cells compared to nasal mucosa. Application of GCs resulted in a significantly higher antiproliferative effect on juvenile angiofibroma versus nasal mucosa fibroblasts in vitro. Conclusion. Expression of GRs and antiproliferative effects of GCs on juvenile angiofibroma fibroblasts offer novel options for the treatment of this unique fibrovascular tumor. V C 2012 Wiley Periodicals, Inc. Head Neck 34: 1615-1621, 2012

BACKGROUND A lot has changed in terms of intervention technique, indications and embolic agents since Duggan introduced embolization to management of postraumatic epistaxis in 1970. Embolization is used in treatment of spontaneous and traumatic epistaxis, palliative tumors and vascular defects, as well as vascularized tumors and juvenile nasopharyngeal angiofibromas. The possibility of simultaneous visualization of pathology and implementation of therapy is one of its greatest advantages. MATERIAL/METHODS Authors analyzed the efficacy of selective embolization treatment of haemorrhage in advanced head and neck tumors. Seventy-six patients with such tumors treated at the Department of Otolaryngology in Bialystok between1999 and 2011 were examined. RESULTS Embolization of bleeding vessel within the tumor was effective (hemorrhage was stopped) in 65 patients (86%). Although the method is highly efficient, it is still associated with complications. Fourteen patients suffered from headaches that lasted for several days and six from face edema. Rebleeding was rare. Unfortunately, there was one case of hemiparesis. CONCLUSIONS We conclude that superselective endovascular treatment deserves to be considered alongside standard options for the palliative or preoperative management of acute hemorrhage from advanced head and neck cancers.

A 24-year-old lady presented with left flank pain of 3 months duration. She had stigmata of tuberous sclerosis complex in the form of angiofibromas on face, ash-leaf macules on back and right upper limb and shagreen patches over back. Computed tomography scan of the abdomen showed 6.5 cm × 5.0 cm × 4.4 cm lobulated intensely enhancing exophytic mass lesion in mid pole of left kidney with significant para-aortic lymphadenopathy with no evidence of fat in the mass. She underwent radical left nephrectomy with a provisional diagnosis of renal cell carcinoma. Histopathological examination showed multicenteric angiomyolipoma involving kidney and para-aortic lymph nodes. This case report underscores the need for further research to differentiate fat-poor angiomyolipoma and lymphadenopathy from renal cell carcinoma.

A 38 year lady had recurrent generalized and myoclonic seizures since 6 years of age. On examination she had facial adenoma sebaceum and periungal fibromas, cutaneous angiofibromas on the back. Contrast enhanced magnetic Resonance Imaging of brain was suggestive of multiple cortical tubers with sub ependymal nodules consistent with the diagnosis of Tuberous sclerosis. Focal hypertrophy of the skin of the dorsal aspect of the left hand with focal gigantism was noted.

Cellular angiofibromas are rare, slow-growing mesenchymal tumours, most often localised in the vulva and perineum of women. We present a case of a 60-year-old male with a 7-cm large cellular angiofibroma in the inguinal canal extending toward the testis, detected after inguinal herniorraphy. Inguinal orchiectomy was performed and the pathology report revealed a cellular angiofibroma containing a lot of mast cells in the stroma, which was collagenised with spindle-shaped cells and characterised by hyalinised vascular structures. The localisation and nature of this type of mass makes initial diagnosis difficult. Differential diagnosis is important to rule out histologically malignant aggressive angiomyxomas and other solitary fibrous tumours. As local recurrence may occur after resection, long-term follow-up is necessary.

Tuberous sclerosis complex (TSC) is an autosomal dominant genodermatosis characterised by the development of hamartomatous tumours in multiple organs including the brain, skin, kidneys, heart and lungs. Facial angiofibromas are the most visible and unsightly of the cutaneous manifestations of TSC, often resulting in stigmatisation for both the affected individuals and their families. Current treatments include vascular laser, ablative lasers and other destructive techniques such as shave excision and electrodessication. For the best outcome these treatments have to be repeated throughout childhood and teenage years, necessitating multiple general anaesthetics. We report a pilot study of topical rapamycin in four children with TSC and facial angiofibromas. Two patients were trialled on 0.1% rapamycin in petrolatum and the other two patients with 0.1% rapamycin solution (Rapamune) applied topically. Both preparations were rapidly and equally effective, however the 0.1% in petrolatum was much better tolerated. Younger patients with smaller angiofibromas had the best response with near complete clearance. Both preparations were more cost effective than pulsed dye laser under general anaesthesia. Although larger studies are needed, this treatment shows a potential to be a first-line management for facial angiofibromas in TSC and appears safe to start in early childhood.

The origin of juvenile angiofibroma is usually around the region of the sphenopalatine artery, and the surgical management of large tumors can be challenging. Traditional approaches to advanced tumors involved open transfacial or transcranial microscope-assisted surgery. Advances in image guidance and endonasal endoscopic techniques have made endonasal endoscopic approaches to the pterygopalatine and infratemporal possible. Endoscopes allow for greater magnification and visualization of complex anatomy, and endoscopic approaches allow the surgeon to avoid manipulation of the osseous midfacial structures that may result in craniofacial abnormalities in this adolescent population.

Object Craniofacial approaches provide excellent exposure to lesions in the anterior and middle cranial fossae. The authors review their experience with craniofacial approaches for resection of large juvenile nasopharyngeal angiofibromas. Methods Between 1992 and 2009, 22 patients (all male, mean age 15 years, range 9–27 years) underwent 30 procedures. These cases were reviewed retrospectively. Results Gross-total resection of 17 (77%) of the 22 lesions was achieved. The average duration of hospitalization was 8.2 days (range 3–20 days). The rate of recurrence and/or progression was 4 (18%) of 22, with recurrences occurring a mean of 21 months after the first resection. All patients underwent preoperative embolization. Nine patients (41%) developed complications, the most common of which was CSF leakage (23%). The average follow-up was 27.7 months (range 2–144 months). The surgery-related mortality rate was 0%. Based on their mean preoperative (90) and postoperative (90) Karnofsky Performance Scale scores, 100% of patients improved or remained the same. Conclusions The authors' experience shows that craniofacial approaches provide an excellent avenue for the resection of large juvenile nasopharyngeal angiofibromas, with acceptable rates of morbidity and no deaths.

Juvenile nasopharyngeal angiofibromas are vascular tumors that may make resection difficult and potentially dangerous. Preoperative embolization is frequently used to decrease surgical morbidity and blood loss. Embolization has typically been performed via a transarterial route using a variety of embolic materials. The authors present a case in which endoscopic assistance was used for direct transnasal tumor puncture and intratumoral embolization using the liquid embolic agent Onyx. In this case there was excellent infiltration of the parenchymal vasculature with complete angiographic obliteration. There were no complications related to the embolization. The tumor was resected with minimal blood loss. To the authors' knowledge, there have been no previous reports of this novel direct intratumoral embolization technique using endoscopic guidance.

Summary Juvenile nasopharyngeal angiofibromas as well as head and neck paragangliomas are rare, benign but aggressive tumours for which surgical resection is the treatment of choice. Tumour resection can be accompanied by significant blood loss and postoperative morbidity. Despite the advances in radiological imaging, embolisation of vascular supply and endoscopic resection, these tumours continue to be a challenge and require multidisciplinary management. The tumours though superficially similar in terms of high vascularity, proximity to neurovascular structures as well as difficult anatomical location require differing anaesthetic management depending on the tumour type and location. There is very little literature available on the anaesthetic management of these tumours which may vary depending on the peculiarities of each tumour. This article aims to familiarize anaesthesiologists with the advances in the perioperative management of these patients.

Background. The main goal of the study was the analysis of somatostatin receptor (SSTR) expression on juvenile na- sopharyngeal angiofibroma (JNA) cells and a subsequent analysis of the utility of SST analog-based scintigraphy in JNA diagnostics. Methods. Nine JNA cases were analyzed. All tissue sam- ples were analyzed for the expression of SSTRs. In 2 cases, scintigraphy was performed after the intravenous (IV) adminis- tration of an SST analog. MRI of the craniofacial region was subsequently performed. Results. The SST analogues were accumulated in areas matching pathologic tissue in the nasopharynx. Immunohisto- chemical evaluation of the tissue samples proved the overex- pression of SSTRs. Conclusions. SSTRs are overexpressed on JNA cells. The SST analog 99m TC-octreotide is effectively bound to JNA cells. SST analogues might be used in the diagnostics and treatment of primary, recurrent, or residual JNA. V C 2011 Wiley Periodi- cals, Inc. Head Neck 33: 1739-1746, 2011

Tuberous sclerosis is an autosomal dominant hereditary condition with many varied forms of clinical presentation. The most frequent cutaneous findings in tuberous sclerosis include multiple angiofibromas, hypopigmented macules, periungual fibromas and shagreen patch. It is characterized by the development of hamartomatous growths in many organs. We present a case of tuberous sclerosis with a giant left internal carotid artery aneurysm causing pulsatile proptosis, left sided ptosis, anisocoria and papillary mydriasis indicative of left third cranial nerve palsy. DOI: http://dx.doi.org/10.3329/bmj.v43i2.21393 Bangladesh Med J. 2014 May; 43 (2): 103-105

Summary Background Patients with tuberous sclerosis complex (TSC) develop fibrous tumours in the brain, skin, kidney, heart and lungs due to TSC1/2 mutations. In the skin, patients develop angiofibromas that have vascular and fibrotic components in which transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-2 are important. Objectives To investigate if the TGF-β axis and MMP-2 play an important role in the pathogenesis of TSC angiofibromas. Methods Samples from TSC angiofibromas and normal skin were measured for expression of TGF-β and MMP-2 by immunohistochemistry and real-time polymerase chain reaction. Fibroblasts grown from TSC angiofibromas (TSC fibroblasts) were incubated with TGF-β. Expression of ERK, AKT and S6K was measured by Western blotting, and MMP-2 expression and activity were determined by enzyme-linked immunosorbent assay and gelatin zymography, respectively. Results There was an increase in the expression of TGF-β and MMP-2 in TSC tumours compared with those in normal skin. The baseline expression of MMP-2 was increased in conditioned medium from TSC fibroblasts. In addition, TGF-β enhanced MMP-2 production and activity, which could be abrogated by pretreatment with an AKT inhibitor (LY294002) but not with rapamycin. Finally, there was a significant colocalization of TGF-β and MMP-2 in the TSC tumours. Conclusions There is an increase of MMP-2 as a result of TGF-β acting through AKT in TSC tumour cells. This regulation of the TGF-β–AKT–MMP-2 axis is independent of mammalian target of rapamycin (mTOR) signalling. In addition to targeting the mTOR pathway, targeting TGF-β simultaneously could block dysregulated tissue remodelling in TSC tumours.

Tuberous sclerosis complex (TSC) is an inherited multisystem disorder; it may involve kidney, brain, skin, lungs, and liver. We report a 37-year-old female TSC patient presenting with skin lesions (angiofibromas, molluscum pendulum). Radiologic examination revealed additional brain and renal lesions consisting of tumors, cysts, and angiomyolipomas. Treatment with rapamycin disclosed improvement in skin lesions. The number and volume of angiofibromas and molluscum pendulum reduced progressively in 6 months. During the ninth month of treatment, magnetic resonance imaging was repeated for renal and brain lesions. Imaging results showed reduction in tumor and angiomyolipoma volumes. Oral rapamycin therapy can improve renal, brain, and skin lesions in TSC disease. Therefore, it may be an alternative therapy for TSC patients.

Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment.To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions.Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC.Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks.The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated."Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P .001), and 60% (95% CI, 41%-77%; P .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment.Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality.ClinicalTrials.gov Identifier: NCT02635789.

Background and Objective Tuberous sclerosis (TS) is a well-described genetic disorder that is classically associated with up to hundreds of facial angiofibromas. Due to the progressive nature of the skin lesions and the early clinical presentation, a safe and effective technique for treating these disfiguring skin lesions is needed. Study Design/Patients and Methods We report a combinatorial technique for treating the angiofibromas of TS. We present a case series of three TS patients treated with this technique combining pinpoint electrosurgery, pulsed-dye laser treatment, and ablative fractional resurfacing (AFR). Results In all presented cases, improvement in the number and appearance of facial angiofibromas and erythema is noted. No scarring or adverse events were reported. Conclusion The technique of electrosurgery, pulsed-dye laser treatment, and AFR represents a new and safe therapeutic option for treating facial angiofibromas associated with TS. Lasers Surg. Med. 42:357–360, 2010. © 2010 Wiley–Liss, Inc.

Before the development of endoscopic skull-based surgical techniques, external surgical approaches with facial incisions often were used to access lesions of the pterygopalatine space (PPS) and beyond. Lesions of the PPS and adjacent skull base areas include juvenile nasal angiofibromas, schwannomas, lymphoma, fungal infections, cerebrospinal fluid (CSF) leaks, and metastatic malignancies. Traditional approaches included midface degloving, lateral rhinotomy with medial maxillectomy, Caldwell-Luc, and subtemporal craniotomy. Recent advances in endoscopic technology, endoscopic instrumentation, and stereotactic navigation have markedly augmented minimally invasive approaches for these pathologies.

Cellular angiofibroma is a mesenchymal neoplasm that is characterized by a bland spindle cell component, morphologically reminiscent of spindle cell lipoma, and thick-walled vessels. The tumor occurs equally in men and women and usually arises in the inguino-scrotal or vulvovaginal regions. An earlier study of 51 cases from our group showed that the tumor follows a benign course without any tendency for recurrence. In 1 case, an intralesional microscopic nodule of pleomorphic liposarcoma was observed. The biologic significance of atypia or sarcomatous transformation in cellular angiofibroma remains uncertain. In this study, we characterized clinicopathologic features in 13 cases of cellular angiofibroma with morphologic atypia or sarcomatous transformation. Thirteen cases with atypia or sarcomatous transformation among 154 usual cellular angiofibromas identified between 1993 and 2009 were retrieved from consultation files. There were 12 females and 1 male ranging in age from 39 to 71 years (median age, 46 y). Tumor size ranged from 1.2 to 7.5 cm. In 11 cases, the tumors occurred in the vulva. One case each occurred in the paratesticular and hip regions. Most tumors were located in subcutaneous tissue. There were 4 cases of cellular angiofibroma with atypia. Three showed severely atypical cells as scattered foci within the cellular angiofibroma. One case showed a discrete nodule of atypical cells. There were 9 cases of cellular angiofibroma with morphologic features of sarcomatous transformation. In each case, abrupt transition to a discrete sarcomatous component was seen. Of these 9 cases, the sarcomatous component in 2 cases showed features of pleomorphic liposarcoma with multivacuolated lipoblasts readily identified. Three of these 9 cases showed discrete nodule(s) closely resembling atypical lipomatous tumor within usual cellular angiofibroma. In the remaining 4 cases, the sarcomatous component was composed of pleomorphic spindle cells arranged in various patterns. By immunohistochemistry, atypical cells and sarcomatous areas showed either multifocal or more diffuse p16 expression compared with either scattered or negative expression in the conventional cellular angiofibroma. The 3 cases with atypical lipomatous tumor-like areas were negative for MDM-2 and CDK4. Follow-up information was available for 7 patients (range from 2 to 75 mo; median: 14 mo). Six patients did not develop recurrence or metastasis. One patient died of metastatic carcinoma of unknown primary site 27 months after the diagnosis of cellular angiofibroma with sarcomatous transformation. Cellular angiofibroma with atypia or morphologic sarcomatous transformation occurs predominantly in the subcutaneous tissue of the vulva and, as yet, shows no evident tendency to recur based on limited clinical follow-up available for 7 cases. The sarcomatous component can show variable features including atypical lipomatous tumor, pleomorphic liposarcoma, and pleomorphic sarcoma NOS. Overexpression of p16 in the atypical cells and sarcomatous component suggests a possible underlying molecular mechanism.

Juvenile nasopharyngeal angiofibromas (JNAs) are rare, benign, but locally invasive vascular lesions that have traditionally been resected using open surgical approaches. However, with the wider availability of superselective intra-arterial embolization, the advent of improved endoscopic, transnasal techniques, and advances in instrumentation, recent years have witnessed a shift toward the use of less invasive, strictly endoscopic methods for the management of such lesions. The purpose of this article is to describe the surgical techniques used in the endoscopic resection of JNAs and to discuss the indications, trends, and current limitations of this approach. As technological advancements and surgical expertise continue to develop, the spectrum of applicability for such endoscopic procedures will undoubtedly broaden to encompass progressively larger, more extensive lesions in the future.

Facial angiofibromas are a major diagnostic sign for tuberous sclerosis (TS) and MEN1, and the former is probably the first disease to be considered by a geneticist when such lesions are found. They occur in up to 90% of persons with TS and 40–80% of individuals with MEN1. Early onset facial angiofibromas that are not associated with any other systemic sign appear to be unusual, and their occurrence can leave the clinician with some uncertainty as to their significance, as well as how to proceed. In this article we describe four patients with what appear to be isolated, bilateral facial angiofibromas. We discuss the significance of these lesions with respect to the conditions in which they have been seen, review prior reports of apparently isolated angiofibromas, and provide some rough calculations as to how likely it would be for an underlying systemic condition to be overlooked after different levels of investigation have been performed. We also look at some aspects of the financial cost/benefit ratio of further investigation of TS beyond a clinical examination. © 2010 Wiley-Liss, Inc.

Esclerose tuberosa é uma condição rara e autossômica dominante. Miofibroblastos são células que exibem fenótipo híbrido entre fibroblastos e células musculares lisas. O objetivo deste caso clínico é mostrar as características clínicas e histopatológicas da esclerose tuberosa e avaliar miofibroblastos nos angiofibromas cutâneos dessa condição. Lesões removidas foram coradas em HE e tricrômico de Masson. Para determinar a presença de miofibroblastos foi usada imunoistoquímica para α-SMA. Essa reação mostrou-se negativa para miofibroblastos. Como α-SMA é um marcador específico para essas células, esse resultado sugere que miofibroblastos não estejam envolvidos com os angiofibromas da esclerose tuberosa descrita. Tuberous sclerosis is a rare autosomal dominant disorder. Myofibroblasts are cells with a hybrid phenotype between fibroblasts and smooth muscle cells. The objective of this study is to describe clinical and histopathological characteristics of tuberous sclerosis and to conduct an immunohistochemical evaluation of myofibroblasts in cutaneous angiofibromas present in this condition. Lesion sections removed were stained with hematoxylin-eosin and Masson's trichrome. Immunohistochemistry against α-SMA was done to determine the presence of myofibroblasts, and the reaction was negative. Since α-SMA is a specific marker for myofibroblasts, this result suggests that myofibroblasts are not involved in cutaneous angiofibromas present in the tuberous sclerosis case reported.

Juvenile nasopharyngeal angiofibromas (JNAs) are rare tumors found exclusively in adolescent boys. Over the last 10 years, endoscopic approaches for resection of JNAs have been used, yielding acceptable results and relatively low recurrence rates. Endoscopic resection preceded by embolization has been shown to be superior to open approaches from a blood loss and hospital stay standpoint. We have performed the first direct intratumoral embolization using the new liquid embolic substance Onyx in cooperation with neurosurgery through endoscopic visualization of the tumor. This article describes our technique for embolization and endoscopic resection of JNAs.

Cellular angiofibroma is a benign vascular neoplasm that typically arises in the vulva, perineal, and paratesticular region. Microscopically the lesions exhibit multiple small, non-dilated capillary channels, many of which contain erythrocytes. The endothelial lining cells are prominent, with monomorphic oval nuclei. Interposed among the vessels are both delicate and mature collagen fibers with fibroblastic hypercellularity that is variable in older lesions where sclerosis is prominent. The lesions usually do not recur following simple excision. Recent evidence indicates that cellular angiofibromas may be cytogenetically related to spindle cell lipoma. This represents the first reported instances of cellular angiofibroma in the oral cavity.

Juvenile nasopharyngeal angiofibromas and paragangliomas are the most common hypervascular tumors of the head and neck that require embolization as an adjunct to surgery. A detailed understanding of the functional vascular anatomy of the external carotid artery is necessary for safe and effective endovascular therapy. Embolization, using a transarterial technique and particulate agents, a direct puncture technique and liquid embolic agents, or both techniques may allow for complete devascularization of hypervascular tumors of the head and neck. Effective embolization of these tumors results in a significant reduction of blood loss during surgery and allows for complete resection of the tumors. Use of meticulous technique and a thorough knowledge of functional anatomy of the head and neck vasculature are essential.

Angiofibromas are highly vascular benign tumors that characteristically arise within the nasopharynx and are predominantly seen to occur in young adolescent males. Extranasopharyngeal angiofibromas are rare with only 56 cases being reported to date. The most common site of presentation for extranasopharyngeal angiofibromas is the maxillary sinus. We report a buccal space angiofibroma excised via an intra-oral route and discuss surgical approaches to the buccal space with a relevant review of literature.

Background. Angiofibromas are histologically benign vascular tumors, originating from the nasopharynx, near by the area of sphenopalatine foramen. These neoplasms occur typically in male adolescents. Reports of primary extranasopharyngeal angiofibromas have appeared sporadically in the literature in English. We present the first case of an elderly woman with tumor arising from the middle turbinate, diagnosed as angiofibroma. Case report. A 63-year-old female presented with left-sided nasal obstruction and epistaxis. Endoscopic evaluation revealed a polypoid mass arising from the anteroinferior portion of the left middle turbinate. Computed tomography (CT) scan showed a soft-tissue opacity that filled the anterior part of the left nasal cavity. After the endoscopic excision of the mass, postoperative pathohistological and immunohistochemical analysis confirmed the diagnosis of an angiofibroma. Two years later, the patient was free of symptoms and without endoscopic evidence of recurrence. Conclusion. Extranasopharyngeal angiofibromas arising from the nasal cavity are extremely rare tumors. Immunohistochemical analysis is very important in all doubtful cases, especially in those with atypical location.