Transanal endoscopic microsurgery resection of rectal tumors: outcomes and recommendations.

PURPOSE: Transanal endoscopic microsurgery provides a minimally invasive alternative to radical surgery for excision of benign and malignant rectal tumors. The purpose of this study was to review our experience with transanal endoscopic microsurgery to clarify its role in the treatment of different types of rectal pathology. METHODS: A prospective database documented all patients undergoing transanal endoscopic microsurgery from October 1996 through June 2008. We analyzed patient and operative factors, complications, and tumor recurrence. For recurrence analysis, we excluded patients with fewer than 6 months of follow-up, previous excisions, known metastases at initial presentation, and those who underwent immediate radical resection following transanal endoscopic microsurgery. RESULTS: Two hundred sixty-nine patients underwent transanal endoscopic microsurgery for benign (n = 158) and malignant (n = 111) tumors. Procedure-related complications (21%) included urinary retention (10.8%), fecal incontinence (4.1%), fever (3.8%), suture line dehiscence (1.5%), and bleeding (1.5%). Local recurrence rates for 121 benign and 83 malignant tumors were 5% for adenomas, 9.8% for T1 adenocarcinoma, 23.5% for T2 adenocarcinoma, 100% for T3 adenocarcinoma, and 0% for carcinoid tumors. All 6 (100%) recurrent adenomas were retreated with endoscopic techniques, and 8 of 17 (47%) recurrent adenocarcinomas underwent salvage procedures with curative intent. CONCLUSIONS: Transanal endoscopic microsurgery is a safe and effective method for excision of benign and malignant rectal tumors. Transanal endoscopic microsurgery can be offered for (1) curative resection of benign tumors, carcinoid tumors, and select T1 adenocarcinomas, (2) histopathologic staging in indeterminate cases, and (3) palliative resection in patients medically unfit or unwilling to undergo radical resection.

Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity.

Brooke-Spiegler syndrome, familial cylindromatosis, and familial trichoepithelioma are autosomal-dominant genetic predispositions for benign tumors of skin appendages caused by mutations in the CYLD gene localized on chromosome 16q12-q13. The encoded protein functions as ubiquitin-specific protease (UBP), which negatively regulates NF-kappaB and c-Jun N-terminal kinase (JNK) signaling. We investigated five families affected with these skin neoplasms and identified four premature stop codons and the novel missense mutation D681G in a family in which 11 of 12 investigated tumors were trichoepitheliomas. CYLD protein harboring this missense mutation had a significant reduced ability to inhibit TNF receptor-associated factor (TRAF)2- and TRAF6-mediated NF-kappaB activation, tumor necrosis factor-alpha (TNFalpha)-induced JNK signaling, and to deubiquitinate TRAF2. CYLD-D681G was coimmunoprecipitated by TRAF2, but was unable to cleave K63-linked polyubiquitin chains. Aspartic acid 681 is highly conserved in CYLD homologues and other members of the UBP family, but does not belong to the Cys and His boxes providing the CYLD catalytic triad (Cys601, His871, and Asp889). As reported previously, the homologous residue D295 of HAUSP/USP-7 forms a hydrogen bond with the C-terminal end of ubiquitin and is important for the enzymatic activity. These results underline that D681 in CYLD is required for cleavage of K63-linked polyubiquitin chains.

Choix thérapeutique dans les tumeurs costales primaires [Therapeutic choice in primary costal tumors].

Primary rib tumors constitute a rare entity and have only seldom been studied separately. In a retrospective study based on 21 cases, with the help of the literature, we try to specify the specific problems encountered with rib tumors and the therapeutic consequences that follow. Our series comprises 10 benign tumors, 3 malignant tumors and 8 cartilaginous tumors. The benign tumors were resected and all the patients recovered uneventfully. One of the patients died of a plasmocytoma 92 months after resection. Among the cartilaginous tumors, we observed two recurrences after 9 and 24 months from which the patient died eventually at 20 and 72 months after resection. The histologic diagnosis of a rib tumor must be made through an excisional biopsy. Cartilaginous tumors are potentially malignant. They must be treated as malignant tumors by radical resection and primary reconstruction. The long-term follow-up of every patient carrying a rib tumor is mandatory because of the risk of late recurrence.

Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and review of literature.

Eyelid tumors are the most common neoplasm in daily ophthalmology practice and encompass a wide variety of benign and malignant tumors. In this retrospective study, we report the clinical and histological features of 5504 eyelid skin tumors diagnosed at the Laboratory of Ophthalmopathology of the Hôpital Ophtalmique Jules Gonin, Lausanne, Switzerland, between January 1989 and December 2007. Benign tumors largely predominated over malignant ones, representing 84% of cases in this series, and the 5 most frequent subtypes were squamous cell papilloma (26%), seborrheic keratosis (21%), melanocytic nevus (20%), hidrocystoma (8%), and xanthoma/xanthelasma (6%). Basal cell carcinoma was the most frequent malignant tumor (86%), followed by squamous cell carcinoma (7%) and sebaceous carcinoma (3%). For several tumor subtypes, there was a poor correlation between clinical and histological diagnosis, stressing the numerous pitfalls in the diagnosis of eyelid tumors. We further discuss our results with reference to previously published series.

Single stage transforaminal retrojugular tumor resection: The spinal keyhole for dumbbell tumors in the cervical spine.

BACKGROUND: Dumbbell tumors are defined as having an intradural and extradural component with an intermediate component within an expanded neural foramen. Complete resection of these lesions in the subaxial cervical spine is a challenge, and it has been achieved through a combined posterior/anterior or anterolateral approach. This study describes a single stage transforaminal retrojugular (TFR) approach for dumbbell tumors resection in the cervical spine. METHODS: This is a retrospective review of a series of 17 patients treated for cervical benign tumors, 4 of which were "true" cervical dumbbell tumors operated by a simplified retrojugular approach. The TFR approach allows a single stage gross total resection of both the extraspinal and intraspinal/intradural components of the tumor, taking advantage of the expanded neural foramen. All patients were followed clinically and radiologically with magnetic resonance imaging (MRI). RESULTS: Gross total resection was confirmed in all four patients by postoperative MRI. Minimal to no bone resection was performed. No fusion procedure was performed and no delayed instability was seen. At follow up, one patient had a persistent mild hand weakness and Horners syndrome following resection of a hemangioblastoma of the C8 nerve root. The other three patients were neurologically normal. CONCLUSIONS: The TFR approach appears to be a feasible surgical option for single stage resection in selective cases of dumbbell tumors of the cervical spine.

Histopathology and prognosis of de novo bladder tumors following solid organ transplantation.

BACKGROUND: Patients following solid organ transplantation have an increased risk of developing de novo bladder tumors, but their biology is poorly characterized. METHODS: We studied 1743 patients who underwent a transurethral resection of a newly diagnosed bladder tumor at a single institution. The histopathology, treatment, recurrence-free survival and overall survival were evaluated and compared between transplant and non-transplant patients. RESULTS: We identified 74 transplant patients who developed a de novo bladder tumor after a median post-transplantation interval of 62 months. The tumor was malignant in 29 patients (39 %). The most common benign lesion was nephrogenic adenoma (84 %), which neither coexisted with nor developed into malignant tumors during follow-up. Compared with non-transplant patients (n = 1669), transplant patients were significantly younger (median 55 vs 69 years, P < 0.001) and had a 9.0-fold higher odds of benign tumors (P < 0.001), while there were no differences in pathology among patients with urothelial carcinoma of the bladder (UCB). In a multivariable analysis for non-muscle-invasive UCB that was adjusted for the risk group, patients with a transplant had a 1.8-fold increased risk of recurrence (P = 0.048). Four of five transplant patients did not respond to Bacillus Calmette-Guérin instillations. There were no differences in overall survival after radical cystectomy (P = 0.87). CONCLUSIONS: The majority of bladder tumors in transplant patients are benign, and they neither coexist with nor develop into malignant tumors. Transplant patients with non-muscle-invasive UCB show an increased risk of disease recurrence, while those treated with radical cystectomy have similar outcomes to patients without a transplant.

Molecular analysis of non-melanoma skin cancer

SUMMARY:Cylindroma, trichoepithelioma and spiradenoma are benign tumors of hair follicle. They are caused by mutations and loss of heterozygosity in the CYLD gene. CYLD is a ubiquitously expressed, but the tumors are restricted to skin, suggesting that the tumorigenesis is influenced by skin-specific regulators and probably by mutations in other genes. The objectives of the thesis were to analyze the molecular mechanisms leading to the aforementioned tumors. In the first project, we have identified five new mutations in CYLD gene in tive families affected with different combinations of these skin appendage tumors. F our of these mutations caused the introduction of a premature stop codon in CYLD protein sequence, but one was a missense mutation changing aspartic acid 681 into glycine (D68lG), in patients exhibiting multiple trichoepitheliomas. CYLD is a deubiquitinase which can downregulate NF-κB and INK pathways through the deubiquitination of TRAF2, for example. We showed that the CYLD-D681G mutant was unable to remove polyubiquitin chains from TRAF2. We also proved that CYLD-D68lG could not inhibit TRAP 2- or TNFα- mediated NF-κB or INK activations in 293T cells. These results underlined the importance of the D68l residue for the enzymatic activity of CYLD. TRAP-interacting protein (TRIP), which is a E3-Ubiquitin ligase, is a partner of CYLD. In the second project of the thesis, we studied the function of TRIP in the epidermis. We found that TRIP was a nucleolar protein in cultured human primary keratinocytes (HEK) and HeLa cells, and was detected in the midbody of HeLa cells. Moreover, TRIP expression was shown to be downregulated through a PKC-dependent mechanism before induction of keratinocyte differentiation. We also proved that TRIP was upregulated in basal cell carcinomas. Furthermore, TRIP was found to be important for keratinocyte survival and proliferation through the regulation of the Gl/S transition. Our results suggest that TRIP may be involved in keratinocyte tumorigenesis.RÉSUMÉ :Les cylindromes, trichoépithéliomes et spiradénomes sont des tumeurs bénignes du follicule pileux causées par des mutations et une perte d'hétérozygotie du gène CYLD. CYLD est ubiquitaire mais les tumeurs sont limitées à la peau, suggérant que la tumorigénèse est influencée par des protéines spécifiques de la peau et par des mutations dans d'autres gènes. Les objectifs de la thèse étaient d'2malyser les mécanismes moléculaires aboutissant à la formation de ces tumeurs. Dans le premier projet, cinq nouvelles mutations du gène CYLD ont été identifiées chez cinq familles présentant différentes combinaisons des tumeurs citées ci- dessus. Quatre de ces mutations causaient I' introduction d'un codon stop prématuré dans la séquence protéique, mais une était une mutation «misser1se» changeant l'aspartate 681 en résidu glycine (D68lG) chez des patients présentant des trichoépithéliomes multiples. CYLD est une déubiquitinase qui inhibe les voies de signalisation de NF-κB et JNK, en déubiquitinant notamment TRAF2. Nous avons montré que la protéine mutante CYLD- D68lG ne pouvait pas cliver la chaîne de poly-ubiquitines liée à TRAF2. CYLD-D68lG était aussi incapable d'inhiber l'activation de NF-κB ou de JNK induite par TRAF2 ou TNF-o dans les cellules 293T. Ces résultats ont donc souligné l'impo1tance du résidu D68l pour l'activité de CYLD. «TRAF-interacting protein (TRIP)», qui est une «E3-ubiquitin-ligase», est un partenaire de CYLD. Dans le second proj et de la thèse, nous avons étudié la fonction de TRIP dans l'épidenne. Nous avons montrépque TRIP était nucléolaire dans les cellules HeLa et les kératinocytes primaires humains en culture et était détectée dans le «midbody» des cellules HeLa. Nous avons prouvé que l'ARNm de TRIP était diminué avant l'induction de la différentiation des kératinocytes, par un mécanisme dépendent de la protéine kinase C, tandis qu'il était augmenté dans les carcinomes baso-cellulaires. Nous avons aussi montré que TRIP influençait la prolifération et la survie des kératinocytes en régulant la transition G1/S, Nos résultats suggèrent que TRIP est peut-être impliquée dans la tumorigénèse des kératinocytes. 7

Epidermal differentiation and carcinogenesis

Summary Skin, and more precisely the epidermis, plays a crucial role in our survival since it constitutes our first line of defense against our environment. A subtle equilibrium between proliferation and differentiation of keratinocytes, the main epidermal cell type, provides a continous self-renewal of the epidermis, maintaining the integrity of this protective barrier. It is now well established that pertubation of the normal balance between proliferation and differentiation can induce development of several diseases including cancer. The aim of my thesis was first to characterize new genes involved in the differentiation process of keratinocytes and the formation of the epidermis. We show that cornulin, encoded by the c1orf10 gene, is a new marker of epidermal differentiation, mainly expressed in the suprabasal layers of the epidermis. Structurally, cornulin belongs to the "fused genes" protein family and contains a functional calcium-binding domain as well as two repeated sequences of 60 amino acids, the function of which remain unknown. The second part of my work aimed to identify new proteins interacting with CYLD. When mutated, CYLD is responsible for cylindromatosis, a predisposition to benign tumors of skin appendages mainly located on the scalp. CYLD is implicated in the NF-κB signalling pathway. We have identified HBO1 and p30, two nuclear proteins, as potential CYLD partners. Since CYLD was described as a negative regulator of NF-icB-mediated transcription, we have tested the putative effect of HBO1 and p30 on the regulation of this signalling pathway. We have shown that only HBO1 is able to inhibit NF-κB-mediated transactivation. The mechanism of action of HBO1 is still under investigation but our results suggest that an unknown cofactor is involved in this process. Résumé La peau est cruciale à notre survie car elle est notre première ligne de défense contre notre environnement. L'épiderme qui forme cette barrière protectrice entre le corps et l'environnement extérieur est continuellement renouvelé suite aux agressions physiques, chimiques et biologiques répétées qu'il subit. Le but de ce renouvellement étant de garantir l'intégrité de cette barrière. Le keratinocyte est le principal type cellulaire trouvé dans l'épiderme. La formation d'une barrière active dépend essentiellement de la faculté des kératinocytes à proliférer et à se différencier. Il est aujourd'hui admis que tout déséquilibre entre l'activité de prolifération et de différenciation des kératinocytes est la cause du développement de plusieurs maladies, dont certains cancers. Le but de ce travail de thèse était, dans un premier temps d'identifier ou de caractériser de nouveaux gènes impliqués dans le processus de différenciation afin de mieux comprendre la formation de l'épiderme. Noús avons ainsi démontré que la cornulin, produit du gène c1orf10, est un nouveau marqueur de la différenciation épidermique, principalement exprimé dans les couches suprabasales de l'épiderme. D'un point de vue structural, nous avons montré que cette protéine appartient à la famille des « fused gene » et qu'elle possède un domaine de liaison au calcium qui est fonctionnel et deux séquences répétées de 60 acides aminés dont la fonction est encore inconnue. La seconde partie de cette thèse était dédiée à l'étude de la cylindromatose, une prédisposition génétique à la formation de tumeurs bénignes, principalement localisées sur la tête et due à des mutations du gène CYLD. Nous avons cherché de nouvelles protéines qui interagissent avec CYLD afin de mieux caractériser les voies de signalisation impliquées dans le développement de la maladie. Nous avons ainsi identifiés deux nouveaux partenaires potentiels de CYLD ; HBO1 et p30 CYLD ayant été décrit comme un régulateur négatif de la transcription médiée par NF-κB; nous avons testé l'implication de HBO1 et p30 au niveau de cette activité transcriptionnelle. Nous montrons que seul HBO1 est capable d'inhiber la transactivation d'un gène rapporteur régulé par NF-κB. Le mécanisme d'action de HBO1 n'est pas encore connu, néanmoins nos résultats suggèrent l'intervention d'un cofacteur qui reste à déterminer.

The role of stereotactic ablative radiotherapy in oncological and non-oncological clinical settings: highlights from the 7th Meeting of AIRO - Young Members Working Group (AIRO Giovani).

Stereotactic ablative radiotherapy is a modern cancer treatment strategy able to deliver highly focused radiation in one or a few fractions with a radical intent in several clinical settings. Young radiation oncologists need a constant and tailored update in this context to improve patient care in daily clinical practice. A recent meeting of AIRO Giovani (AIRO - Young Members Working Group) was specifically addressed to this topic, presenting state-of-the-art knowledge, based on the latest evidence in this field. Highlights of the congress are summarized and presented in this report, including thorough contributions of the speakers dealing with the role of stereotactic ablative radiotherapy in both oncological and non-oncological diseases, divided according to anatomical and clinical scenarios: intra-cranial settings (brain malignant primary tumors, metastases, benign tumors and functional disorders) and extra-cranial indications (lung primary tumors and metastases, thoracic re-irradiation, liver, lymph node and bone metastases, prostate cancer). With literature data discussed during the congress as a background, stereotactic ablative radiotherapy has proved to be a consolidated treatment approach in specific oncological and non-oncological scenarios, as well as a promising option in other clinical settings, requiring a further prospective validation in the near future. We herein present an updated overview of stereotactic ablative radiotherapy use in the clinic.

Different locations of dermoid cysts in the orbital region.

BACKGROUND: Dermoid cysts are frequent unilateral congenital benign tumors that can be found at different locations throughout the body. In the orbital region, dermoid cysts occur predominantly in the supero-temporal quadrant. However, different orbital locations are possible, making this entity an important differential diagnosis for orbital tumors. PATIENTS AND METHODS: We retrospectively reviewed the charts of 23 consecutive patients operated in our institution between 2005 and 2014 for orbital tumors that were diagnosed as congenital dermoid or epidermoid cysts. RESULTS: There were 21 dermoid and 2 epidermoid cysts. The median age at surgery time was 7 years (range 1-41). There were 15 females and 8 males. Eleven cysts were located supero-temporally (47.8%), seven supero-medially (30.4%), two temporally (8.7%), one at the frontal bone (4.4%) and two in the fossa of the lacrimal gland (8.7%). The mean cyst diameter was 13.1 mm±5.0 (SD). None had signs of malignant disease. No recurrence was observed after complete excision. CONCLUSION: Dermoid cysts of orbital region are mostly located in the supero-temporal quadrant. However, other orbital locations are possible and dermoid cysts must thus be considered in the differential diagnosis of any mass in the orbital region.

Keratoacanthoma: a distinct entity?

Keratoacanthoma (KA) are common but exceptional benign tumors, often appearing on sun-exposed areas of light skinned people and showing spontaneous resolution. The goal of this study was to review existing literature, to point out the etiological complexity of KA biology and to answer the controversial debate if or not KA is a distinct entity or a variant of squamous cell carcinoma (SCC). Relying on recent results, we highlight that KA is an individual lesion with a unique molecular signature caused by alterations in the TGFβ signalling pathway. These recent findings will help to understand the nature of KA and to develop new reliable diagnostic tools, simplifying the discrimination of the histologically similar KA and SCC.

Gamma Knife radiosurgery in benign skull base tumors after planned subtotal resection: preliminary results in combined approaches

Aim: The management of large lesions of the skull base, such as vestibular schwanommas (VS), meningiomas (MEN) or pituitary adenomas (PA), is challenging, with microsurgery remaining the main treatment option. Planned subtotal resection is now being increasingly considered to reduce the risk of neurological deficits following complete resection. The residual part of the tumor can then be treated with Gamma Knife Radiosurgery (GKR) to achieve long-term growth control. Methods: This case series documents early results with planned subtotal resection followed by GKR in Lausanne University Hospital, between July 2010 and March 2012. There were 24 patients who underwent surgery, with 22 having already undergone GKR and 2 waiting for GKR. We analyzed clinical symptoms for all patients, as well as audiograms, ophthalmological and endocrinological tests, when indicated. Results: Nine patients had VS surgery (mean diameter 35 mm; range 30-44.5) through a retrosigmoid approach. There were no post-operative facial nerve deficits. Of the 3 patients whom had useful hearing pre-operatively, this improved in 2 and remained stable in 1. Four patients with clinoid MEN (mean diameter 26.5 mm; range 17-42) underwent subtotal resection of the tumor, and the component in the cavernous sinus was later treated with GKR. The visual status remained stable in 3 patients and one had complete visual recovery. 4 patients underwent subtotal resection of petro-clival MEN (mean diameter 36 mm; range 32-42): 3 had House-Brackmann (HB) grade 2 facial function that recovered completely; one continues to have HB grade 4 facial deficit following surgery. Of the 7 patients with PA (mean diameter 34.5 mm; range 20-54.5), 2 had acromegaly, the others were non functional PA. Six patients underwent trans-sphenoidal surgery, while one patient had a transcavernous sinus resection of the tumor (with prior staged trans-sphenoidal surgery). Visual status improved in 3 patients while the others remained stable. Two patients had transient diabetes insipidus following surgery. Up to now, no additional deficit or worsening has been reported after GKR. Conclusions: Our data suggest that planned subtotal resection has an excellent clinical outcome with respect to preservation of cranial nerves, and other neurological functions, and a good possibility of recovery of many of the pre-operative cranial nerve dysfunctions. The results in terms of tumor control following GKR need further long-term evaluation.

Cellular schwannomas of the intracranial and intraspinal compartment: morphological and immunological characteristics compared with classical benign schwannomas.

The concept of cellular schwannoma as an unusual benign tumor is well established for peripheral nerves but has never been tested in neurosurgical series. In order to test the validity of this concept in cranial nerves and spinal roots we performed an analysis of the clinical and morphological characteristics of 12 cellular and 166 classical benign schwannomas. Immunohistochemical detection of antigen expression in Schwann cells including proliferating cell nuclear antigen (PCNA) was also performed. This study shows that cellular schwannomas in neurosurgical series manifest at a lower age than the classical benign variant and occur mainly in the spinal roots. Mitotic activity and sinusoidal vessels appear more frequently in cellular schwannomas and constitute with high cellularity, the most valuable criteria separating both entities. The postoperative course in both types of tumors was free of metastases or sarcomatous changes. Immunoexpression of S-100 protein, vimentin, epithelial membrane antigen and glial fibrillary acidic protein is not statistically different between the two variants. In contrast, PCNA is more highly expressed in cellular schwannomas. These These results confirm the concept that cellular schwannomas are a clinico-pathological variant of benign schwannomas and provide significant support for the introduction of this entity in neurosurgical oncology.