Well-differentiated Squamous Cell Carcinoma With Sarcomatous Differentiation in Patient With a History of Recurrent Verrucous Carcinoma.

Human papillomavirus-independent vulvar squamous cell carcinoma has a peak incidence in about the eighth decade of life. A variable portion of the vulvar squamous cell carcinoma are human papillomavirus-independent comprising 20% to 80% of all cases. Verrucous carcinoma (VC) is part of the spectrum of human papillomavirus-independent carcinomas and its combination with well-differentiated squamous cell carcinoma with sarcomatous differentiation is an extremely unusual neoplasm. The available literature on VC is currently limited to case reports and small single-institution studies. Here, we present a case concerning an 81-year-old woman with a history of chronic itching, swelling, and lichen sclerosis with variable-sized multiple white-pink plaques of the vulva. The pathologic diagnosis of VC was made. The patient later on developed multiple lesions of biopsy proved VC and most recent biopsy shows well-differentiated squamous cell carcinoma with abrupt sarcomatous differentiation. A review of the literature shows the rarity of this lesion of the female genital tract. Clinicians and patients should be aware of the aggressive behavior of cancers and adjust their surgical management together with the follow-up strategy. To the best of our knowledge, this is the first description of a VC and well-differentiated squamous cell carcinoma with abrupt sarcomatous differentiation occurring in the vulva.

Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon.

Cereblon (CRBN), a substrate receptor for the cullin-RING ubiquitin ligase 4 (CRL4) complex, is a direct protein target for thalidomide teratogenicity and antitumor activity of immunomodulatory drugs (IMiDs). Here we report that glutamine synthetase (GS) is an endogenous substrate of CRL4(CRBN). Upon exposing cells to high glutamine concentration, GS is acetylated at lysines 11 and 14, yielding a degron that is necessary and sufficient for binding and ubiquitylation by CRL4(CRBN) and degradation by the proteasome. Binding of acetylated degron peptides to CRBN depends on an intact thalidomide-binding pocket but is not competitive with IMiDs. These findings reveal a feedback loop involving CRL4(CRBN) that adjusts GS protein levels in response to glutamine and uncover a new function for lysine acetylation.