bims-netuvo 2023-07-16 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2023–07–16
nine papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Pancreatic ductal adenocarcinoma induces neural injury that promotes a transcriptomic and functional repair signature by peripheral neuroglia.
Pancreatic Tumor-Derived Extracellular Vesicles Stimulate Schwann Cell Phenotype Indicative of Perineural Invasion via IL-8 Signaling.
Risk Stratification by Quantification of Perineural Cancer Invasion on Prostate Needle Core Biopsy: Should It Be Counted?
Three-dimensional analysis of perineural invasion in extrahepatic cholangiocarcinoma using tissue clearing.
Recurrent Basal Cell Carcinoma (BCC) of the Forearm: A Case Report.
Prognostic Impact of Tumor Budding on Moroccan Gastric Cancer Patients.
Giant schwannoma on the lower leg: A case report and review of the literature.
Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs.
Factors predicting recurrence in benign spinal nerve sheath tumors: A retrospective study of 457 patients from a single institution.

Oncogene. 2023 Jul 11.

Pancreatic ductal adenocarcinoma induces neural injury that promotes a transcriptomic and functional repair signature by peripheral neuroglia.

Jonathan Weitz, Bharti Garg, Alexei Martsinkovskiy, Sandip Patel, Herve Tiriac, Andrew M Lowy.

Perineural invasion (PNI) is the phenomenon whereby cancer cells invade the space surrounding nerves. PNI occurs frequently in epithelial malignancies, but is especially characteristic of pancreatic ductal adenocarcinoma (PDAC). The presence of PNI portends an increased incidence of local recurrence, metastasis and poorer overall survival. While interactions between tumor cells and nerves have been investigated, the etiology and initiating cues for PNI development is not well understood. Here, we used digital spatial profiling to reveal changes in the transcriptome and to allow for a functional analysis of neural-supportive cell types present within the tumor-nerve microenvironment of PDAC during PNI. We found that hypertrophic tumor-associated nerves within PDAC express transcriptomic signals of nerve damage including programmed cell death, Schwann cell proliferation signaling pathways, as well as macrophage clearance of apoptotic cell debris by phagocytosis. Moreover, we identified that neural hypertrophic regions have increased local neuroglial cell proliferation which was tracked using EdU tumor labeling in KPC mice, as well as frequent TUNEL positivity, suggestive of a high turnover rate. Functional calcium imaging studies using human PDAC organotypic slices confirmed nerve bundles had neuronal activity, as well as contained NGFR+ cells with high sustained calcium levels, which are indicative of apoptosis. This study reveals a common gene expression pattern that characterizes solid tumor-induced damage to local nerves. These data provide new insights into the pathobiology of the tumor-nerve microenvironment during PDAC as well as other gastrointestinal cancers.

DOI: https://doi.org/10.1038/s41388-023-02775-7
bioRxiv. 2023 Jun 28. pii: 2023.06.26.546629. [Epub ahead of print]

Pancreatic Tumor-Derived Extracellular Vesicles Stimulate Schwann Cell Phenotype Indicative of Perineural Invasion via IL-8 Signaling.

Emory Gregory, Isabel Powers, Azemat Jamshidi-Parsian, Robert Griffin, Younghye Song.

Pancreatic cancer remains a pre-eminent cause of cancer-related deaths with late-stage diagnoses leading to an 11% five-year survival rate. Moreover, perineural invasion (PNI), in which cancer cells migrate into adjacent nerves, occurs in an overwhelming majority of patients, further enhancing tumor metastasis. PNI has only recently been recognized as a key contributor to cancer progression; thus, there are insufficient treatment options for the disease. Attention has been focused on glial Schwann cells (SC) for their mediation of pancreatic PNI. Under stress, SCs dedifferentiate from their mature state to facilitate the repair of peripheral nerves; however, this signaling can also re-direct cancer cells to accelerate PNI. Limited research has explored the mechanism that causes this shift in SC phenotype in cancer. Tumor-derived extracellular vesicles (TEV) have been implicated in other avenues of cancer development, such as pre-metastatic niche formation in secondary locations, yet how TEVs contribute to PNI has not been fully explored. In this study, we highlight TEVs as initiators of SC activation into a PNI-associated phenotype. Proteomic and pathway assessments of TEVs revealed an elevation in interleukin-8 (IL-8) signaling and nuclear factor kappa B (NFκB) over healthy cell-derived EVs. TEV-treated SCs exhibited higher levels of activation markers, which were successfully neutralized with IL-8 inhibition. Additionally, TEVs increased NFκB subunit p65 nuclear translocation, which may lead to increased secretion of cytokines and proteases indicative of SC activation and PNI. These findings present a novel mechanism that may be targeted for the treatment of pancreatic cancer PNI.
Statement of Significance: Identifying pancreatic tumor extracellular vesicles as key players in Schwann cell activation and perineural invasion by way of IL-8 will educate for more specialized and effective targets for an under-valued disease.

DOI: https://doi.org/10.1101/2023.06.26.546629
J Urol. 2023 Jul 11. 101097JU0000000000003618

Risk Stratification by Quantification of Perineural Cancer Invasion on Prostate Needle Core Biopsy: Should It Be Counted?

Yuki Teramoto, Ying Wang, Hiroshi Miyamoto.

   PURPOSE: We assessed the prognostic significance of quantification of perineural invasion (PNI) on prostate biopsy (PBx).
MATERIALS AND METHODS: We quantified actual PNI foci in the entire PBx specimens from 724 patients and compared corresponding radical prostatectomy (RP) findings and long-term oncologic outcomes.
RESULTS: No PNI was detected in 524 (72.4%) PBxs, whereas 1 (≥129; 17.8%), 2 (n=40; 5.5%), 3 (n=18; 2.5%), 4 (n=7; 1.0%), and 5-10 (n=6; 0.8%) PNI foci were present in other cases. We confirmed a higher risk of recurrence after RP in patients with PNI on PBx than in those with no PNI (P < .001). Remarkably, recurrence-free survival was comparable between those with 0 vs 1 PNI (P = .9) or 2 vs ≥3 PNIs (P = .3). Nonetheless, multifocal PNI per PBx (vs single PNI; P < .001) and >1 PNI per 10-mm tumor (vs ≤1 PNI; P = .008) were associated with worse outcomes. Interestingly, in a subgroup outcome analysis of single vs multifocal PNI per PBx, there was a significant difference in patients showing PNI involving only 1 of sextant sites. In multivariable analysis, both multifocal PNI/case (HR=5.48, P < .001) and >1 PNI/10-mm tumor (HR=3.96, P < .001) showed significance for recurrence. Meanwhile, compared with CAPRA score alone (0.687/0.685), Harrell's c-index/AUC for predicting 5-year recurrence-free survival were gradually increased when 1 (0.722/0.740), 2 (0.747/0.773), or 3 (0.760/0.792) point(s) were additionally assigned to multifocal PNI.
CONCLUSIONS: Multifocal PNI and >1 PNI per 10-mm tumor on each PBx were thus found to be associated with poorer prognosis, as independent predictors, in men with prostate cancer undergoing RP.

Keywords:  needle biopsy; perineural invasion; prognosis; prostate cancer; radical prostatectomy

DOI:  https://doi.org/10.1097/JU.0000000000003618
Pathol Oncol Res. 2023 ;29 1611284

Three-dimensional analysis of perineural invasion in extrahepatic cholangiocarcinoma using tissue clearing.

Hirokazu Ogasawara, Tadashi Yoshizawa, Kiyoko Oshima, Kenta Ogasawara, Shunsuke Kubota, Shintaro Goto, Satoko Morohashi, Taiichi Wakiya, Norihisa Kimura, Keinosuke Ishido, Hiroshi Kijima, Kenichi Hakamada.

  Perineural invasion (PNI) is a characteristic invasion pattern of distal cholangiocarcinoma (DCC). Conventional histopathologic examination is a challenging approach to analyze the spatial relationship between cancer and neural tissue in full-thickness bile duct specimens. Therefore, we used a tissue clearing method to examine PNI in DCC with three-dimensional (3D) structural analysis. The immunolabeling-enabled 3D imaging of solvent-cleared organs method was performed to examine 20 DCC specimens from five patients and 8 non-neoplastic bile duct specimens from two controls. The bile duct epithelium and neural tissue were labeled with CK19 and S100 antibodies, respectively. Two-dimensional hematoxylin/eosin staining revealed only PNI around thick nerve fibers in the deep layer of the bile duct, whereas PNI was not identified in the superficial layer. 3D analysis revealed that the parts of DCC closer to the mucosa exhibited more nerves than the normal bile duct. The nerve fibers were continuously branched and connected with thick nerve fibers in the deep layer of the bile duct. DCC formed a tubular structure invading from the epithelium and extending around thin nerve fibers in the superficial layer. DCC exhibited continuous infiltration around the thick nerve fibers in the deep layer. This is the first study using a tissue clearing method to examine the PNI of DCC, providing new insights into the underlying mechanisms.

Keywords:  cholangiocarcinoma; iDISCO; perineural invasion; three-dimensional; tissue clearing

DOI:  https://doi.org/10.3389/pore.2023.1611284
Cureus. 2023 Jun;15(6): e40247

Recurrent Basal Cell Carcinoma (BCC) of the Forearm: A Case Report.

Safaa Abatli, Mohammed Hasan, Suha B Sholi, Ahmad Qashoo, Iyad Maqboul.

  We describe a case of basal cell carcinoma (BCC) in a 36-year-old lady. She had a history of recurrent BCC in the ventral aspect of her right forearm. She presented to our hospital with her third recurrence of skin lesions in the same location. Histopathological examination of the skin revealed the features of BCC with evidence of perineural invasion (PNI). She underwent a margin-free, wide local excision, vacuum-assisted closure of the wound, and reconstructive surgery using a skin graft. She also underwent a sentinel lymph node biopsy (SLNB), which was negative for the tumor. Then she was referred for radiotherapy. Although the patient underwent a free-margin excision in the previous episodes, she came back years later with a recurrent lesion. It is considered that basal cell carcinomas larger than 3 cm in size with perineural invasion evidence on histopathological examination and with deep tissue involvement have a bad prognosis compared with the smaller superficial lesions. Thus, based on the findings in our case and the previously reported cases, careful follow-up is recommended for patients with BCC with bad prognostic factors. In certain high-risk cases, SLNB should be considered to rule out occult metastasis.

Keywords:  agressive bcc; bcc of forearm; forearm reconstruction; perineural invasion of bcc; reconstruction after bcc excision; recurrent bcc

DOI:  https://doi.org/10.7759/cureus.40247
Clin Pathol. 2023 Jan-Dec;16:16 2632010X231184329

Prognostic Impact of Tumor Budding on Moroccan Gastric Cancer Patients.

Souhaila El Yaagoubi, Meryem Zaryouhi, Soumaya Benmaamar, Fatima El Agy, Layla Tahiri El Ousrouti, Nawal Hammas, Hicham El Bouhaddouti, Zineb Benbrahim, Nada Lahmidani, Laila Chbani.

   Background: Tumor budding (TB) has been defined as an independent prognostic factor in many carcinomas like colon adenocarcinoma, but its prognostic impact on gastric cancer patients remains not well established. In the present study, we aimed to highlight the correlation of tumor budding with clinicopathological features and predict its survival outcomes in gastric cancer patients for the first time in the Moroccan population.
Methods: This study was conducted on 83 patients who underwent surgery for gastric adenocarcinoma from 2014 to 2020. The patient's clinico-pathological characteristics were obtained from the pathological and clinical records of each patient. Tumor budding was assessed on HES slides, according to the 2016 International Tumor Budding Consensus Conference criteria. The association of tumor budding grades with categorical and continuous variables were respectively assessed by the χ2-test and the unpaired t-test. Survival analysis was performed by the Kaplan-Meier method, the log-rank test.
Results: Patients consisted of 65.1% of men and 34.9% of women with a median age of 61.2 years. Histologically, the majority of the tumors were adenocarcinoma (65.1%). Among all cases, 18.1% were classified as Bud1 (15/83), (27/83) 32.5% as Bud 2, and 49.4% (41/83) as Bud 3 grades. High-grade tumor budding (BUD 3) was found to be significantly associated with special clinicopathological features including older age (P = .02), unradical resection (R1/R2) (P = .03), and the presence of vascular invasion (P = .05), and perineural invasion (P = .04). Furthermore, tumors with high-grade tumor budding were significantly associated with a low rate of resected lymph nodes (P = .04) and advanced TNM stage (P = .02). Among all stages, high-grade tumor budding was correlated with shorter overall survival in univariate and multivariate analysis (P = .04). Patients with high-tumor budding had worse relapse-free survival compared with patients with low-tumor budding grade (P = .01).
Conclusion: According to our study, the high-tumor budding grade was correlated with unfavorable clinicopathological features and poorer survival. The present study findings suggest that tumor budding should be considered in the treatment and prognosis of gastric cancer patients.

Keywords:  Gastric cancer; survival; tumor budding

DOI:  https://doi.org/10.1177/2632010X231184329
Int J Surg Case Rep. 2023 Jul 06. pii: S2210-2612(23)00597-7. [Epub ahead of print]109 108468

Giant schwannoma on the lower leg: A case report and review of the literature.

Vinh Pham Quang, Huy Hoang Quoc, Bach Nguyen, Chuong Ngo Quang, Hieu Nguyen Chi, Ngoc Nguyen.

   INTRODUCTION AND IMPORTANCE: Peripheral nerve sheath tumors are common neoplasm with different biological features ranging from benign to malignant. The majority of these tumors are smaller than 5 cm, whereas those larger are termed giant schwannomas. When localized in the lower legs, the maximum length of the schwannoma is less than 10 cm. We report a case of giant schwannoma of the leg and its management.
CASE PRESENTATION: A 11-year-old boy presented with a 13 cm × 5 cm firm, smooth, well-defined margin mass in the posterior-medial aspect of right leg. The tumor was fusiform, well capsulated, multi-lobulated soft tissue with 13 cm × 4 cm × 3 cm in size at the biggest region. On MRI the tumor was low signal, isointense with adjacent tissue on T1S, hyper-intense on T2-FS sequences and surrounded by a thin fat-like intense rim. Biopsy findings were considered most consistent with Schwannoma (Antoni A). Tumor resection was performed. The mass appeared capsulated, white, and glistening with 132 mm × 45 mm × 34 mm in size. Postoperative course was uneventful without neurological deficit.
CLINICAL DISCUSSION AND CONCLUSION: Schwannomas are the most common peripheral nerve sheath tumors that derived almost entirely from Schwann cells. Schwannomas usually affect the head and neck region, localization in the lower extremity is rare. When located in lower extremity, the maximum diameter of 5 cm is described in most studies. Clinical presentation of schwannomas is unclear and unspecific. Diagnosis is based on ultrasound, MRI, and histology. The recommended treatment for schwannoma is surgical enucleation or resection without damaging the involved nerve.

Keywords:  Enucleation; Giant schwannoma

DOI:  https://doi.org/10.1016/j.ijscr.2023.108468
Neuro Oncol. 2023 Jul 12. pii: noad121. [Epub ahead of print]

Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs.

Erik A Williams, Ajay Ravindranathan, Rohit Gupta, Nicholas O Stevers, Abigail K Suwala, Chibo Hong, Somang Kim, Jimmy Bo Yuan, Jasper Wu, Jairo Barreto, Calixto-Hope G Lucas, Emily Chan, Melike Pekmezci, Philip E LeBoit, Thaddeus Mully, Arie Perry, Andrew Bollen, Jessica Van Ziffle, W Patrick Devine, Alyssa T Reddy, Nalin Gupta, Kristen Basnet, Robert Macaulay, Patrick Malafronte, Han Lee, William H Yong, Kevin Jon Williams, Tareq A Juratli, Douglas A Mata, Richard S P Huang, Matthew C Hiemenz, Dean C Pavlick, Garrett M Frampton, Tyler Janovitz, Jeffrey S Ross, Susan M Chang, Mitchel S Berger, Line Jacques, Jun S Song, Joseph F Costello, David A Solomon.

   BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here we sought to further define the molecular pathogenesis of schwannomas.
METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.
RESULTS: We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from non-vestibular cranial nerves (e.g. facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.
CONCLUSIONS: We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

Keywords:   PMP2 ; SOX10 ; Schwann cell; myelination; schwannoma

DOI:  https://doi.org/10.1093/neuonc/noad121
J Clin Neurosci. 2023 Jul 10. pii: S0967-5868(23)00165-0. [Epub ahead of print]114 158-165

Factors predicting recurrence in benign spinal nerve sheath tumors: A retrospective study of 457 patients from a single institution.

A R Prabhuraj, Sarthak Mehta, Nishanth Sadashiva, Nupur Pruthi, Arivazhagan Arima, Kannepalli Narasingha Rao, Vikas Vazhayil, Manish Beniwal, Abhinith Shashidhar, Gyani Jail Singh Birua, Sampath Somanna.

   BACKGROUND: Benign Nerve sheath tumors (NST) comprise almost one-third of primary spinal tumours. The majority are sporadic. They have low rates of recurrence but an occasional recurrence may need re-surgery. The present study was designed to identify the variables that can predict the risk of their recurrence.
METHODS: A retrospective chart review was done including all the histologically proven benign spinal NSTs operated between 2001 and 2019 in our institute. Demographic, operative and postoperative follow-up data were recorded. Recurrence was defined as local reappearance after definite surgical excision or symptomatic increase in size of a residual tumour on follow-up imaging studies. Statistical analysis was done to determine the significant variables associated with local recurrence.
RESULTS: 457 patients with a median age of 38 years operated for 459 NSTs qualified for the study. The most frequent location of occurrence of tumours was found to be Low Cervical level (C3-C7 levels). Majority of Schwannoma were located intradurally while Neurofibroma were dumb-bell shaped and extradural. Most of the tumours had solid consistency. Post operatively, 7.7% patients developed complications. 7.8% tumours developed local recurrence after median period of 12 months. The patients developing recurrence were younger compared to nonrecurring tumors. On univariate analysis, male gender, Low cervical and Cervicothoracic junction location were associated with higher recurrence. On multivariate analysis, location at Cervicothoracic junction reached significance.
CONCLUSION: Overall recurrence risk among all NST was 7.8% with a median progression free survival of 36 months. The location of tumour at cervicothoracic location was the significant risk factors for recurrence of tumour in our study.

Keywords:  Intradural extramedullary tumour; Nerve sheath tumours; Neurofibroma; Neurofibromatosis; Schwannoma

DOI:  https://doi.org/10.1016/j.jocn.2023.06.019