Targeted analysis of Ubiquitin-Specific Peptidase (USP8) in a population of Iranian people with Cushing's disease and a systematic review of the literature.

OBJECTIVE: Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. METHODS: Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. RESULTS: In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. CONCLUSION: Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.

A rare presentation of Rosai-Dorfman disease as a single dural-based lumbar intradural lesion: A case report.

Central nervous system Rosai Dorfman disease (RDD) is a rare condition and it is just reported in 5% of 600 registered RDD cases. In previously reported patients, the intradural extramedullary spinal lesion is extremely rare. In this article, we aim to report a case of intradural extramedullary Rosai-Dorfman lesion of the lumbar spine which was managed with gross total resection. Lumbar meningioma was the pre-operative diagnosis for this patient, the final correct diagnosis of Rosai-Dorfman disease was made after histological examination. RDD should be considered in the differential diagnosis of single intradural extramedullary lesions of the lumbar spine.

Cell proliferation, apoptosis, and angiogenesis in non-functional pituitary adenoma: association with tumor invasiveness.

PURPOSE: Non-functioning pituitary adenoma (NFPA) is the most prevalent pituitary macroadenoma. No prognostic marker has been found to explain the behavior of these tumors. We aimed to explore cell proliferation, apoptosis, proangiogenic markers, and microvascular density (MVD) in noninvasive and invasive NFPAs. METHODS: Adenoma invasiveness was defined according to Knosp and Hardy classifications based on preoperative magnetic resonance imaging scans. Cell proliferation was examined using Ki67 and P53. Tissue expression of Bcl-2 was used to assess the antiapoptosis pathway. CD34 and CD105 were measured to evaluate MVD, while VEGF expression was assessed as an indicator of pro-angiogenesis. Moreover, VEGF, bFGF, endocan, and endostatin were measured on preoperative serum samples. RESULTS: Tissue and serum markers were examined in 18 patients with invasive and 21 patients with noninvasive NFPAs. Ki67 less than 3% was reported in 10 invasive and 14 noninvasive NFPAs (P = 0.752). P53 staining was negative in all subjects. In addition, Bcl-2 staining was negative in 15 and 20 subjects, respectively (P = 0.718). VEGF-A expression 2+ or 3+ was reported in 9 invasive and 11 noninvasive macroadenomas (P = 0.83). Moreover, CD34 and CD105 positivity were comparable between the two groups. Furthermore, the comparison of serum markers showed no significant differences. CONCLUSION: Cell proliferation, apoptosis, and angiogenesis play a limited role in NFPA behavior.

Usefulness of prolactin measurement in inferior petrosal sinus sampling with desmopressin for Cushing's syndrome.

Background: Bilateral inferior petrosal sinus sampling (IPSS) is used to distinguish pituitary from ectopic adrenocorticotropin (ACTH) excess in patients with ACTH-dependent Cushing's syndrome. Our objective was to examine the utility of prolactin measurement during IPSS with desmopressin (DDAVP) stimulation in localization of the source of ACTH excess.Method: Retrospective review of 20 patients with ACTH-dependent Cushing's syndrome who underwent IPSS with DDAVP stimulation. Baseline, DDAVP-stimulated, and prolactin-normalized ACTH IPS:P (inferior petrosal sinus to peripheral) ratios were calculated. Cut-off values for each test were obtained from receiver-operating characteristic (ROC) curve analysis.Results: Fifteen patients had Cushing disease (CD), and five were diagnosed with ectopic ACTH syndrome (EAS). For the baseline ACTH IPS:P ratio of ≥2, the diagnostic sensitivity (80%), specificity (100%), positive predictive value (PPV) (100%) and negative predictive value (NPV) (62.5%) were calculated. These values for DDAVP-stimulated IPS:P ACTH ratio ≥ 3, were 86.7%, 100%, 100% and 71.4%, respectively. The corresponding value for the prolactin-normalized ACTH IPS:P ratio ≥ 0.8 were 86.6%, 80%, 92.8% and 66.7%. The cut-off value for the baseline, DDAVP-stimulated and prolactin-normalized ACTH IPS:P ratios were 1.76, 3.9, and 0.33, respectively.Conclusion: Prolactin-normalized ACTH IPS:P ratio measurement showed comparable sensitivity and less specificity than baseline/DDAVP-stimulated IPS/P ACTH ratios. Moreover, when baseline and stimulated IPS/P ACTH tests were discordant, prolactin-normalized ACTH IPS: P ratio correctly localized the source of ACTH excess. The sensitivity of the test increased, applying a prolactin-normalized ACTH IPS: P ratio ≥0.33.

A Sporadic Desmoid Tumor: an Exceptional Pancreatic Cystic-Solid Mass.

Desmoid tumors are locally aggressive and non-metastatic neoplasms with a high rate of recurrence. Desmoid tumors of the pancreas are, however, very rare, and only a few cases have been reported in the literature. This paper reports an anecdotal case of a diffuse pancreatic desmoid tumor with the involvement of the pancreatic head, body, and-partially-tail. The patient underwent the Whipple procedure and subtotal pancreatectomy. Histopathological assessment showed that the tissues were partly positive for smooth muscle actin, but not for S100 or PanCK. The Ki67 index of the cells was only 1 %. Unfortunately, the patient died on the 10th postoperative day due to massive upper gastrointestinal bleeding.

Primary bone marrow lymphoma: an uncommon extranodal presentation of aggressive non-hodgkin lymphomas.

Bone marrow involvement by lymphoma is considered a systemic dissemination of the disease arising elsewhere, although some tumors may arise primarily in the bone marrow microenvironment. Primary bone marrow lymphoma (PBML) is a rare entity whose real boundaries and clinicobiological significance are not well defined. Criteria to diagnose PBML encompass isolated bone marrow infiltration, with no evidence of nodal or extranodal involvement, including the bone, and the exclusion of leukemia/lymphomas that are considered to primarily involve the bone marrow. Twenty-one out of 40 lymphomas retrospectively reviewed by the International Extranodal Lymphoma Study Group from 12 institutions in 7 different countries over a 25-year period fulfilled the inclusion criteria. These cases comprised 4 follicular lymphomas (FLs), 15 diffuse large B-cell lymphomas (DLBCLs), and 2 peripheral T-cell lymphomas, not otherwise specified. The FL cases showed paratrabecular infiltration, BCL2 protein and CD10 expression, and BCL2 gene rearrangement. DLBCL showed nodular infiltration in 6 cases and was diffuse in 9 cases; it also showed positivity for BCL2 protein (9/10) and IRF4 (6/8). Median age was 65 years with male predominance. All but 3 FL patients were symptomatic. Most cases presented with cytopenias and high lactate dehydrogenase. Four patients (3 FL cases and 1 DLBCL case) had leukemic involvement. Most DLBCL patients received CHOP-like or R-CHOP-like regimens. The outcome was unfavorable, with a median overall survival of 1.8 years. In conclusion, PBML is a very uncommon lymphoma with particular clinical features and heterogenous histology. Its recognition is important to establish accurate diagnosis and adequate therapy.