The role of SOX9 in non-small cell lung cancer progression is histopathology-selective

The transcription factor SOX9 is a key regulator of multiple developmental processes, and is frequently re-expressed in non-small cell lung cancer (NSCLC). Its precise role in the progression of NSCLC histopathologies has however remained elusive. We show that SOX9 expression relates to poor outcome and invasive histopathology in human adenocarcinomas, and is absent in murine early minimally invasive and human in situ adenocarcinoma. Interestingly, despite wide SOX9 expression across advanced NSCLC histotypes, its genetic deletion in the murine KrasG12D;Lkb1-/- model selectively disrupted only the growth of papillary NSCLC, without affecting the initiation of precursor lesions or growth of mucinous or squamous tissue. Spatial tissue phenotyping indicated a requirement of SOX9 expression for the progression of surfactant protein C-expressing progenitor cells, which gave rise to papillary tumours. Intriguingly, while SOX9 expression was dispensable for squamous tissue formation, its loss in fact led to enhanced squamous tumour metastasis, which was associated with altered collagen IV deposition in the basement membrane. Our work therefore demonstrates histopathology-selective roles for SOX9 in NSCLC progression, namely a requirement for papillary adenocarcinoma progression, but opposing metastasis-suppressing function in squamous histotype tissue. This attests to a pleiotropic SOX9 function, linked to the cell of origin and microenvironmental tissue contexts.

Loss of histone variant macroH2A2 expression associates with progression of anal neoplasm

AimsThe macroH2A histone variants are epigenetic marks for inactivated chromatin. In this study, we examined the expression of macroH2A2 in anal neoplasm from anal intraepithelial neoplasia (AIN) to anal squamous cell carcinoma (SCC).MethodsAIN and anal SCC samples were analysed for macroH2A2 expression, HIV and human papilloma virus (HPV). The association of macroH2A2 expression with clinical grade, disease recurrence, overall survival and viral involvement was determined.ResultsmacroH2A2 was expressed in normal squamous tissue and lower grade AIN (I and II). Expression was lost in 38% of high-grade AIN (III) and 71% of anal SCC (p=0.002). Patients with AIN with macroH2A2-negative lesions showed earlier recurrence than those with macroH2A2-positive neoplasm (p=0.017). With anal SCC, macroH2A2 loss was more prevalent in the HPV-negative tumours.ConclusionsLoss of histone variant macroH2A2 expression is associated with the progression of anal neoplasm and can be used as a prognostic biomarker for high-grade AIN and SCC.

Osteoradionecrosis and cholesteatoma of external auditory canal in postradiotherapy nasopharyngeal carcinoma patien

Background: Osteoradionecrosis and cholesteatoma of the external auditory canal following external-beam radiotherapy as the treatment of nasopharyngeal carcinoma is a rarely found complication. Patients with external auditory canal cholesteatoma (EACC) typically present with chronic otorrhea and dull pain due to the local invasion of squamous tissue into the bony external audioty canal (EAC). Purpose: To remind ENT specialists and general practitioners about the risk osteoradionecrosis and cholesteatoma of external auditory canal in nasopharyngeal carcinoma patient after radioteraphy treatment. Case: We report a case of osteoradionecrosis andcholesteatoma of EAC in nasopharyngeal carcinoma (NPC) patient with complaint of a foul-smelling discharge from her right and left ears. Two years previously she had undergone external-beam radiotherapy to the neck as the treatment for nasopharyngeal carcinoma. Management: The cholesteatoma was removed microscopicaly on local anasthesia. After the cholesteatoma had been removed the right ear result of pure tone audiometry showed mild degree conductive hearing loss (27,7 dB), while the left ear within normal hearing threshold. Conclusion: Osteoradionecrosis and cholesteatoma of external auditory canal could develop as a complication ofradioteraphy in nasopharyngeal carcinoma patient. Keywords: osteoradionecrosis, cholesteatoma, radiotherapy, chronic otorrhea.ABSTRAKLatar belakang: Komplikasi osteoradionekrosis dan kolesteatoma pada liang telinga luar akibat radioterapi pada pengobatan karsinoma nasofaring sangat jarang terjadi. Pasien dengan kolesteatoma liang telinga luar biasanya datang dengan keluhan otore kronis dan nyeri akibat invasi dari jaringan skuamus ke tulang liang telinga luar. Tujuan: Memberi wawasan bagi dokter umum dan spesialis THT-KL tentang adanya risiko osteoradionekrosis dan kolesteatoma pada liang telinga luar akibat radioterapi pada penderita karsinoma nasofaring. Kasus: Dilaporkan satu kasus osteoradionekrosis dan kolesteatoma di liang telinga luar pada penderita karsinoma nasofaring dengan keluhan sekret telinga berbau busuk pada liang telinga kanan dan kiri.Dua tahun sebelumnya pasien tersebut mendapat radioterapi untuk pengobatan karsinoma nasofaring. Penatalaksanaan: Kolesteatoma diangkat secara mikroskopis dengan anestesi lokal. Pemeriksaan audiometri nada murni pascatindakan didapati tuli konduktif derajat ringan (27,7dB) pada telinga kanan sedangkan telinga kiri dalam batas normal. Kesimpulan: Radionekrosis dan kolestatoma liang telinga luar merupakan komplikasi terapi radiasi pada kasus karsinoma nasofaring.Kata kunci: osteoradionekrosis, kolesteatom, radioterapi, otore kronis.

Delineating Molecular Mechanisms of Squamous Tissue Homeostasis and Neoplasia: Focus on p63

Mouse models have informed us that p63 is critical for normal epidermal development and homeostasis. The p53/p63/p73 family is expressed as multiple protein isoforms due to a combination of alternative promoter usage and C-terminal alternative splicing. These isoforms can mimic or interfere with one another, and their balance ultimately determines biological outcome in a context-dependent manner. While not frequently mutated, p63, and in particular the ΔNp63 subclass, is commonly overexpressed in human squamous cell cancers.In vitrokeratinocytes and murine transgenic and transplantation models have been invaluable in elucidating the contribution of altered p63 levels to cancer development, and studies have identified the roles for ΔNp63 isoforms in keratinocyte survival and malignant progression, likely due in part to their transcriptional regulatory function. These findings can be extended to human cancers; for example, the novel recognition of NFκB/c-Rel as a downstream effector of p63 has identified a role for NFκB/c-Rel in human squamous cell cancers. These models will be critical in enhancing the understanding of the specific molecular mechanisms of cancer development and progression.

Cholesteatoma of the Frontal and Ethmoid Areas

Cholesteatomas of the frontoethmoid region must always be considered in the differential diagnosis of a mass in the frontoethmoid region. A painless, slow-growing mass, often accompanied by proptosis and diplopia, but without history of trauma or infection, should make one suspect of this pathologic entity. Although histologically a benign lesion, the keratinizing squamous epithelial lining will continue to desquamate and expand, leading to erosion of surrounding structures which could be life-threatening. In order to prevent recurrence, complete removal of the cyst lining is mandatory. Cosmetic reconstruction, often requiring obliteration of the surgical cavity, should be delayed for one year to insure against recurrence of the covering of active squamous tissue adjacent to dura, cribriform plate or ocular structures.