MAB21L4 Deficiency Drives Squamous Cell Carcinoma via Activation of RET.

Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. In SCC organoids and in vivo tumor models, genetic disruption of RET or selective inhibition of RET with BLU-667 (pralsetinib) suppressed SCC growth while inducing concomitant differentiation. Overall, loss of MAB21L4 early during SCC development blocks differentiation by increasing RET expression. These results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC. SIGNIFICANCE: Downregulation of RET mediated by MAB21L4-CacyBP interaction is required to induce epidermal differentiation and suppress carcinogenesis, suggesting RET inhibition as a potential therapeutic approach in squamous cell carcinoma.

The Adult Neck Mass: Predictors of Malignancy.

OBJECTIVE: Distinguishing benign from malignant adult neck masses can be challenging because data to guide risk assessment are lacking. We examined patients with neck masses from an integrated health system to identify patient and mass factors associated with malignancy. STUDY DESIGN: Retrospective cohort. SETTING: Kaiser Permanente Northern California. METHODS: The medical records of adults referred to otolaryngology in 2017 for a neck mass were evaluated. Bivariate and multivariable logistic regression analyses were performed. RESULTS: Malignancy was found in 205 (5.0%) of the cohort's 4103 patients. Patient factors associated with malignancy included sex, age, and race/ethnicity. Males had more than twice the odds of malignancy compared with females (adjusted odds ratio [aOR] = 2.38). Malignancy rates increased with age, ranging from 2.1% for patients younger than 40 years to 8.4% for patients 70 years or older. White non-Hispanic patients had 1.75 times the risk of malignancy compared with patients of other race/ethnicities. The percentage of patients with malignancy increased with increasing minimum mass dimension, from 3.0% in patients with mass size <1 cm to over 31% in patients with mass sizes 2 cm or larger (P < .0001). Imaging-based mass factors most highly predictive of malignancy included larger minimum mass dimension (≥1.5 cm vs <1.5 cm: aOR = 3.87), multiple masses (2 or more vs 1: aOR = 5.07), and heterogeneous/ill-defined quality (aOR = 2.57). CONCLUSION: Most neck masses referred to otolaryngology were not malignant. Increasing age, male sex, white non-Hispanic ethnicity, increasing minimum mass dimension, multiple neck masses, or heterogeneous architecture/ill-defined borders were associated with malignancy.

Craniofacial Actinomyces osteomyelitis evolving from sinusitis.

Craniofacial Actinomyces osteomyelitis progression is rare, as patients are soon treated. A 56-year-old male smoker presented with sinusitis and was managed medically. This patient failed to follow up and presented 1 year later with erosive bony disease. He was managed medically and surgically; however, his disease evolved to include his midface, skull base, and cranium. He underwent staged debridement and free tissue reconstruction. His disease is controlled but not cured. The literature includes case reports and small series describing limited disease treated successfully with surgical and medical management. Although craniofacial Actinomyces osteomyelitis is uncommon, it can become debilitating. This case demonstrates how craniofacial Actinomyces osteomyelitis can progress and highlights the benefit of a multidisciplinary approach.