The evolution of two transmissible cancers in Tasmanian devils.

Tasmanian devils have spawned two transmissible cancer lineages, named devil facial tumor 1 (DFT1) and devil facial tumor 2 (DFT2). We investigated the genetic diversity and evolution of these clones by analyzing 78 DFT1 and 41 DFT2 genomes relative to a newly assembled, chromosome-level reference. Time-resolved phylogenetic trees reveal that DFT1 first emerged in 1986 (1982 to 1989) and DFT2 in 2011 (2009 to 2012). Subclone analysis documents transmission of heterogeneous cell populations. DFT2 has faster mutation rates than DFT1 across all variant classes, including substitutions, indels, rearrangements, transposable element insertions, and copy number alterations, and we identify a hypermutated DFT1 lineage with defective DNA mismatch repair. Several loci show plausible evidence of positive selection in DFT1 or DFT2, including loss of chromosome Y and inactivation of MGA, but none are common to both cancers. This study reveals the parallel long-term evolution of two transmissible cancers inhabiting a common niche in Tasmanian devils.

The differentiation state of the Schwann cell progenitor drives phenotypic variation between two contagious cancers.

Contagious cancers are a rare pathogenic phenomenon in which cancer cells gain the ability to spread between genetically distinct hosts. Nine examples have been identified across marine bivalves, dogs and Tasmanian devils, but the Tasmanian devil is the only mammalian species known to have given rise to two distinct lineages of contagious cancer, termed Devil Facial Tumour 1 (DFT1) and 2 (DFT2). Remarkably, DFT1 and DFT2 arose independently from the same cell type, a Schwann cell, and while their ultra-structural features are highly similar they exhibit variation in their mutational signatures and infection dynamics. As such, DFT1 and DFT2 provide a unique framework for investigating how a common progenitor cell can give rise to distinct contagious cancers. Using a proteomics approach, we show that DFT1 and DFT2 are derived from Schwann cells in different differentiation states, with DFT2 carrying a molecular signature of a less well differentiated Schwann cell. Under inflammatory signals DFT1 and DFT2 have different gene expression profiles, most notably involving Schwann cell markers of differentiation, reflecting the influence of their distinct origins. Further, DFT2 cells express immune cell markers typically expressed during nerve repair, consistent with an ability to manipulate their extracellular environment, facilitating the cell's ability to transmit between individuals. The emergence of two contagious cancers in the Tasmanian devil suggests that the inherent plasticity of Schwann cells confers a vulnerability to the formation of contagious cancers.

Extracellular vesicle proteomes of two transmissible cancers of Tasmanian devils reveal tenascin-C as a serum-based differential diagnostic biomarker.

The iconic Tasmanian devil (Sarcophilus harrisii) is endangered due to the transmissible cancer Devil Facial Tumour Disease (DFTD), of which there are two genetically independent subtypes (DFT1 and DFT2). While DFT1 and DFT2 can be differentially diagnosed using tumour biopsies, there is an urgent need to develop less-invasive biomarkers that can detect DFTD and distinguish between subtypes. Extracellular vesicles (EVs), the nano-sized membrane-enclosed vesicles present in most biofluids, represent a valuable resource for biomarker discovery. Here, we characterized the proteome of EVs from cultured DFTD cells using data-independent acquisition-mass spectrometry and an in-house spectral library of > 1500 proteins. EVs from both DFT1 and DFT2 cell lines expressed higher levels of proteins associated with focal adhesion functions. Furthermore, hallmark proteins of epithelial-mesenchymal transition were enriched in DFT2 EVs relative to DFT1 EVs. These findings were validated in EVs derived from serum samples, revealing that the mesenchymal marker tenascin-C was also enriched in EVs derived from the serum of devils infected with DFT2 relative to those infected with DFT1 and healthy controls. This first EV-based investigation of DFTD increases our understanding of the cancers' EVs and their possible involvement in DFTD progression, such as metastasis. Finally, we demonstrated the potential of EVs to differentiate between DFT1 and DFT2, highlighting their potential use as less-invasive liquid biopsies for the Tasmanian devil.

Risk of Intracranial Extension of Craniofacial Dermoid Cysts.

BACKGROUND: Dermoid cysts are benign lesions lined by keratinizing squamous epithelium that also contain epidermal adnexa (hair follicles, hair shafts, sebaceous glands, and both apocrine and eccrine sweat glands) and mesodermal derivatives (smooth muscle fibers, vascular stroma, nerves, and collagen fibers). Craniofacial dermoid cysts represent approximately 7 percent of all dermoids and have an incidence ranging between 0.03 and 0.14 percent. METHODS: The authors conducted a single-center, consecutive, nonrandomized comparative case series over a 20-year period of all patients treated surgically for craniofacial dermoid at the Royal Children's Hospital in Melbourne, Australia. Six hundred forty-seven patients had craniofacial dermoids and adequate information to be included in the study. The authors also conducted a thorough review of the literature using the MEDLINE and Embase databases. RESULTS: Six hundred forty-seven patients amounted to 655 lesions in our case series. The age at surgery ranged from 2 months to 18 years, with an average age of 25.65 months. The depth of the lesions was stratified using a classification system, and the risk of intracranial extension was assessed using these data. Midline nasal lesions are established as high risk by other studies, but frontal, temporal, and occipital lesions were found to be as risky if not more risky for intracranial extension. CONCLUSIONS: Several classification systems for craniofacial dermoid cysts have used both broader anatomical locations and physical characteristics to group these lesions and identify those warranting preoperative imaging. The authors propose a system using more specific classification of anatomical location to assist in the prompt identification of high-risk lesions and facilitate sound preoperative planning. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Histological intralesional heterogeneity of actinic keratoses relates to field cancerization.

BACKGROUND/OBJECTIVES: Histological heterogeneity within distinct actinic keratosis (AK) lesions has been described and might serve as an additional feature of AKs. We aimed to investigate and quantify the histological heterogeneity of AKs regarding different grading systems. METHODS AND MATERIAL: We assessed the histology of 3 mm biopsies of AK lesions located on the scalp or face. We documented basal proliferation (PRO I-III), histological grade (AK I-III) and determined the overall classification of each lesion. RESULTS: Of the 305 lesions included, 48 (15.7 %) lesions were classified as AK I, 152 (49.8 %) as AK II and 105 (34.4 %) as AK III. 33 AKs (10.8 %) showed no basal proliferation, 94 (30.8 %) were graded as PRO I, 99 (32.5 %) as PRO II and 79 (25.9 %) as PRO III. One histological grade and basal growth pattern per lesion was observed in 94 (30.8 %) and 104 (34.1 %) cases respectively, two grades in 170 (55.7 %) and 168 (55.1 %) cases, and three grades in 41 (13.4 %) and 33 (10.8 %) cases (Chi-squared test, p < 0.0001). CONCLUSIONS: By analogy with the clinical heterogeneity of field cancerization, AKs show a high histological grade heterogeneity even within small lesions. Variations in AK grading reflect the heterogeneity of the cancerization field and might serve as additional feature.

Petrous Face Meningiomas: Classification, Clinical Syndromes, and Surgical Outcomes.

BACKGROUND: Petrous face meningiomas (PFMs) are challenging tumors because of their proximity to the cranial nerves, brainstem, and critical vasculature. The objective of this study is to present surgical outcomes and support an anatomic classification for PFM based on clinical presentation. METHODS: A retrospective chart review was performed, and 51 PFMs were identified. Tumors were classified by location along the petrous face into anterior, middle, and posterior. Presentation and outcomes were analyzed with logistic regression. RESULTS: The median follow-up was 31.6 months. Tumors were World Health Organization grade I (n = 50), with 1 World Health Organization grade II tumor. Location was anterior (22%), middle (14%), posterior (53%), and overlapping (12%). Median tumor diameter was 3.0 cm (range, 0.8-6.2 cm). Anterior location was associated with facial pain/numbness on presentation (P < 0.0001), middle location with hearing loss/vestibular dysfunction (P = 0.0035), and posterior with hydrocephalus (P = 0.0190), headache (P = 0.0039), and vertigo (P = 0.0265). Extent of resection was gross total (63%), near total (14%), and subtotal (25%). The observed radiographic recurrence rate was 15%. Mean progression-free survival after diagnosis was 9.1 years with 2-year, 5-year, and 10-year progression-free survival of 91.8%, 78.6%, and 62.9%, respectively. The complication rate was 27%. Age, location, and approach were not associated with complications. CONCLUSIONS: PFMs present with distinct clinical syndromes based on their location along the petrous face: anterior with trigeminal symptoms, middle with auditory/vestibular symptoms, and posterior with symptoms of mass effect/hydrocephalous. Surgical resection is associated with excellent long-term survival and a low rate of recurrence, which can be managed with radiotherapy.

Tubulopapillary Cystic Adenoma With Apocrine Differentiation: A Unifying Concept for Syringocystadenoma Papilliferum, Apocrine Gland Cyst, and Tubular Papillary Adenoma.

Syringocystadenoma papilliferum (SCAP), apocrine gland cyst (AGC, also called apocrine hidrocystoma or apocrine cystadenoma), and tubular papillary adenoma (TPA) with apocrine differentiation are defined as proliferations of apocrine epithelium with myoepithelial cells. At Sapporo Dermatopathology Institute, we retrieved 308 benign neoplastic lesions diagnosed as SCAP, AGC, or TPA and combinations of these entities. Among the 308 lesions, 202 (66%) exhibited features of only one type, of which 144 (47%) were AGC, 39 (13%) were TPA, and 19 (6%) were SCAP. The other 106 lesions (34%) had features of 2 or more types, including 56 lesions that were AGC + TPA (18%), 2 that were AGC + SCAP (1%), 34 that were TPA + SCAP (11%), and 14 that were AGC + TPA + SCAP (5%). The most frequent site of these lesions was the face (56%), followed by the scalp (13%). Lesions with the features of AGC were more frequently found on the face, especially the periocular region, than at other sites. TPA lesions were more frequent on the face and scalp than at other sites, whereas SCAP lesions were preferentially found on the face, scalp, and trunk. We also retrieved clinicopathological data and other information. We propose a unifying concept for AGC, TPA, and SCAP. Approximately one-third of these lesions are composite entities with the features of 2 or 3 different tumors, and we propose calling such tumors tubulopapillary cystic adenoma with apocrine differentiation.

Prevalence of osteoma cutis in the maxillofacial region and classification of its radiographic pattern in cone beam CT.

BACKGROUND: Osteoma cutis is a rare soft tissue ossification of cutaneous tissue and may be primary or secondary. In the majorityof cases it is clinically asymptomatic and may detected incidentally on radiographic examination. Cone beam computed tomography (CBCT) has can be of great assistance in the detection of this asymptomatic lesion. OBJECTIVES: In this retrospective study, the prevalence and different radiographic appearance of osteoma cutis was evaluated. MATERIALS AND METHODS: A total of 6,500 CBCT images were evaluated for the presence of osteoma cutis. Ectopic existence of calcified tissue within the soft tissue of the dermis or epidermis that was incompatible with the calcification of other anatomic structures or soft tissue calcifications was considered to be osteoma cutis. Accordingly, the detected patterns were divided into four distinct groups: (1) a single nodule, (2) plate-like lesion, (3) single or multiple depth lesion(s), trans-epidermal, and (4) multiple, disseminated lesions of various sizes known as multiple miliary. The data were evaluated in terms of prevalence and variations. The frequency, total prevalence, percentage and the prevalence of different radiographic forms of this lesion were calculated. RESULTS: One hundred and forty eight (2.27%) cases of 6,500 evaluated tomograms had osteoma cutis. Of these, 5 (0.07%) were in the form of a single nodule, 4 (0.06%) were single, plate-like lesions, 7 (0.1%) were multiple plate-like lesions, 2 (0.03%) were in the form of a deep thread-like lesion, and 130 (2%) presented as multiple disseminated lesions. CONCLUSION: According to the radiographic views, osteoma cutis may be categorized into single nodular, single or multiple plate- like, deep, and multiple disseminated forms. Of the mentioned radiogarphic patterns, the multiple disseminated form (miliary) hada higher prevalence in our study. CBCT images enable accurate evaluation of the nature and frequency of osteoma cutis.

[Fibrohistiocytic tumors of the skin: a heterogeneous group of superficially located mesenchymal neoplasms]. / Fibrohistiozytäre Tumoren der Haut: Eine heterogene Gruppe oberflächlich lokalisierter mesenchymaler Neoplasien.

So-called fibrohistiocytic tumors of the skin comprise a heterogeneous spectrum of superficially located neoplasms that often show fibroblastic and/or myofibroblastic differentiation. In this review clinicopathologically important variants of dermatofibroma and dermatofibrosarcoma protuberans and their differential diagnoses are discussed in detail. In addition, the clinicopathological features of atypical fibroxanthoma, angiomatoid fibrous histiocytoma, plexiform fibrohistiocytic tumors and pleomorphic dermal sarcoma are presented. Entities that have to be considered in the differential diagnosis are also mentioned.

Expression of p53, D2-40 and α-smooth muscle actin in different histological subtypes of facial basal cell carcinoma.

Although, generally BCC growths slowly and is minimally invasive, tumors developed in the head and neck region behave more aggressively with deep tissue invasion, recurrence and even local or distant metastases, causing significant morbidity or mortality. Recently, numerous studies have been conducted in order to identify new prognostic markers of BCC aggressiveness, but the results are not consistent. Thus, we were interested here in the immunohistochemical investigation of p53, D2-40 and α-SMA expression in the aggressive forms (eight infiltrative-morpheaform, six micronodular and six metatypical cases) versus superficial facial BCCs (five cases). As results, we first noticed that p53, D2-40 and α-SMA expression varied between different types of investigated BCCs. The highest reactivity was observed in metatypical subtype for the D2-40. p53 was mainly expressed in the micronodular BCC subtype and on overall, the tumor reactivity to this marker correlated directly with the reactivity for the other two used biomarkers. The infiltrative-morpheaform facial BCCs were peculiar more reactive to α-SMA. For all three investigated markers, regardless the histological subtype, the tumor reactivity was higher at the advancing edge, and in addition, at this level we noticed a D2-40 and α-SMA stromal reactivity for some cases of the more aggressive BCC subtype (peculiar in metatypical subtype). Thus, we concluded that in order to identify the most aggressive forms of facial BCCs it is useful to investigate these three markers, and this is even more important as they can all constitute therapeutic targets.

Hemangioma: review of literature.

Hemangiomas are tumors identifed by rapid endothelial cell proliferation in early infancy, followed by involution over time. All other abnormalities are malformations resulting from anomalous development of vascular plexuses. The malformations have a normal endothelial cell growth cycle that affects the veins, the capillaries or the lymphatics and they do not involute. Hemangiomas are the most common tumors of infancy and are characterized by a proliferating and involuting phase. They are seen more commonly in whites than in blacks, more in females than in males in a ratio of 3:1.

Unilesional follicular mycosis fungoides: report of two cases with progression to tumor stage and review of the literature.

Mycosis fungoides (MF) is the most common type of cutaneous lymphoma and has protean clinicopathological manifestations. Follicular or folliculotropic MF (FMF) is a rare variant, which histopathologically is characterized by pronounced folliculotropism of neoplastic T cells, with or without follicular mucinosis, and clinically by an impaired prognosis compared to classic MF. In contrast, unilesional MF is a very rare variant with an excellent prognosis, with a single case of large-cell transformation reported to date. The combination of folliculotropic and unilesional MF is very unusual, with only two cases reported to date. Here we report two patients with unilesional folliculotropic MF with progression to tumor stage in both patients. To the best of our knowledge, this is the first report on the disease evolution with large-cell transformation and progression of unilesional FMF. Complete remission was achieved by local radiation therapy in both patients. The differential diagnoses, classification and implications for the treatment of unilesional FMF as well as the pertinent literature are discussed.

[Classification of the formations from blood vessels of maxillofacial region and neck in children].

Multidisciplinary group of investigators basing upon special literature study, analysis of their own observation (1168 cases) including retrospective for 20 years and with the help of several following methods - clinical, roentgenological, pathomorphological,immunohistochemical - picked out from wide group of the so called hemangiomas 3 types of lesions: hyperplasia, malformation, tumour and suggested their clinical biological classification. To each of lesion types characteristic was given.

Tumor maligno rabdoide primitivo de maxilar inferior / Primitive malignant rhabdoid tumor of the mandible

El término tumor rabdoide fue utilizado en un comienzo para neoplasias renales con inclusiones citoplasmáticashialinas, que corresponden ultraestructuralmente a filamentos intermedios. Inicialmente descrito en 1978 como una variante rabdosarcomatoide del tumor de Wilms, separándose tres años después por presentar diferencias clinicopatológicas.Después de la descripción clinicohistológica del tumor rabdoide a nivel renal se han descrito tumoresmorfológicamente idénticos en tejidos blandos y órganos. La cavidad oral no es la excepción y han aparecido informes de carcinoma escamocelular con fenotipos rabdoides orales documentados en el año 1996.Se informa este caso debido a su rareza y su origen primario en el maxilar inferior.

Angiographic classification and sclerotic therapy of maxillofacial cavernous haemangiomas: a report of 204 cases.

A total of 204 patients with maxillofacial cavernous haemangiomas were examined by digital subtraction angiography to investigate the factors affecting therapeutic outcome and to optimize treatment selection. Cavernous haemangiomas were classified as high- or low-drainage based on the nature of the draining veins. Patients were randomized to receive either embolization of the draining veins with absolute ethanol followed by bleomycin A5 hydrochloride intra-tumoural injection, or intra-tumoural injection only. In patients with high-drainage haemangiomas (n = 140), there were significant improvements in the complete cure rate and the overall effective rate in those who had received embolization prior to intra-tumoural injection compared with those who had received intra-tumoural injection only. In patients with low-drainage haemangiomas (n = 64), there were no significant differences between the two treatment groups. It is concluded that embolotherapy of draining veins prior to hydrochloride injection is effective for treating high-drainage cavernous haemangiomas whereas bleomycin A5 hydrochloride injection alone is suitable for treating low-drainage cavernous haemangiomas.

Lymphoepithelioma-like carcinoma of the skin: new case of an exceedingly rare primary skin tumor.

Lymphoepithelioma-like carcinoma of the skin (LE-lCS) is a very rare, primary skin neoplasm of uncertain origin. The tumor reveals striking morphological similarity to undifferentiated nasopharyngeal carcinoma (lymphoepithelioma). However, the primary skin tumors have never been associated with Epstein-Barr virus (EBV), in contrast to those at some extracutaneous sites. Since the first description by Swanson et al. in 1988, only 46 cases have been documented over the last 20 years. This case report presents an 89-year-old woman with a 0.5 cm plaque-like, discolored lesion on her left cheek of one-month duration. The patient underwent surgical excision and is disease free one year later. The histopathological, immunohistochemical and EBV in situ hybridization features are described. The clinical and pathological differential diagnosis is discussed. This case supports the contention that LE-lCS is not associated with EBV.

Siringoma condroide de la región maseterina: revisión de la bibliografía y presentación de un caso clínico / Chondroid syringoma of the masseteric region: review of the literature and report of a clinical case

El siringoma condroide es un tumor anexial de muy baja frecuencia de aparición, correspondiendo al 0,01% de los tumores primarios de piel.Es una entidad análoga al adenoma pleomorfo de glándulas salivales.El diagnóstico clínico es prácticamente inexistente debido a la ausencia de características morfológicas distintivas.El tratamiento es quirúrgico.

[Cavernous hemangiomas of the skin of the face and neck and the oral soft tissues].

The structure, clinical manifestations, behavior of cavernous hemangomas of the skin of the face and neck, and the oral soft tissues were studied, by using biopsy specimens from 229 patients. Three types of cavernous hemagiomas of these areas were identified. Their preferred treatments were defined and pathogenetically warranted.

[State of the art of classification, diagnostics and therapy for cervicofacial hemangiomas and vascular malformations]. / "State of the Art" zur Klassifikation, Diagnostik und Therapie von zervikofazialen Hämangiomen und vaskulären Malformationen.

The successful treatment of vascular anomalies depends on profound knowledge of the biologic behavior of vascular lesions and their correct classification. On the base of the clinical course Mulliken and Glowacki developed a biologic classification that was accepted as official classification by the ISSVA (International Society for the Study of Vascular Anomalies). Based on an extended literature research, this manuscript will give an overview of different internationally accepted treatment concepts. Even if a wait-and-see strategy can be recommended in many cases of uneventful hemangiomas in infants the proliferative growth of such lesions requires an adequate treatment indication. Vascular malformations that persist lifelong require treatment in the majority of the cases, especially when clinical symptoms occur. Based on individual parameters such as the diameter, location or growth behavior, different therapeutic options as cryotherapy, corticosteroids, laser therapy, sclerotherapy, surgical intervention and/or embolisation can be performed successfully. None of those treatment concepts, however, represents the only treatment method of choice.