A DSTYK mutation activates ERK1/2 signaling to promote intraspinal dissemination in a case of solitary fibrous tumor/hemangiopericytoma.

Intracranial solitary fibrous tumors/hemangiopericytomas (SFT/HPCs) are vascular tumors that have a high rate of local recurrence and extracranial metastases. Intradural extramedullary spinal dissemination of intracranial SFT/HPC is extremely rare. There is a paucity of data available to elucidate the molecular mechanisms of intraspinal dissemination of intracranial SFT/HPC. Herein, we presented a case of intracranial SFT/HPC with intraspinal metastasis. The resected tumor specimens were enrolled in a clinical sequencing program, including whole-exome and transcriptome sequencing. By comparing genomic sequencing data of the intracranial tumors with intraspinal metastasis, we established the somatic mutational profiles of these tumors. Clonality analysis revealed a distinct subclonal structure in the intracranial tumor and its intraspinal metastasis, which might reflect the possibility of intratumoral clonal selection and evolution during the process of tumor dissemination. Through bioinformatics analysis and Sanger sequencing validation, a DSTYK mutation (Met296Ile) was identified as a candidate driver of intraspinal metastasis in this SFT/HPC case. Further, an intracranial tumor-derived SFT/HPC cell line, HPC3, was established to explore the mechanisms of the DSTYK mutation in promoting SFT/HPC metastasis. Based on the HPC3 cell model, we found that the DSTYK mutation promoted cell migration and invasion of HPC3 cells via activation of ERK1/2 signaling, which was inhibited by the MEK/ERK inhibitor AZD6244. The DSTYK mutation was also shown to upregulate the expression of two metastasis-related molecules: MMP2 and MMP9 in HPC3 cells; however, this effect was attenuated by AZD6244 treatment. Therefore, the DSTYK mutation may activate ERK1/2/MMP2/9 signaling to promote tumor cell metastasis in SFT/HPC. In conclusion, our study revealed the potential role of DSTYK mutation in the regulation of intraspinal metastasis of SFT/HPC, which might provide new biological insights into this rare disease.

Multiple secondary cauda equina non-Hodgkin's lymphoma: a case report and literature review.

BACKGROUND: Secondary central nervous system involvement of non-Hodgkin's lymphoma (NHL) is rare and with poor prognosis, the most common pathological type is diffuse large B cell lymphoma (DLBCL). Although it can occur in any part of central nervous system, it rarely directly infiltrates the spinal cord or cauda equina. CASE PRESENTATION: We present the case of 64-year-old immunocompetent man with a worsening pain of waist and left lower extremity, accompanied by numbness and paresis of bilateral lower extremity for 20 days. His previous medical history included a resection of painless mass in the left groin in another hospital 7 months ago, and the pathological diagnosis was non-Hodgkin small B cell lymphoma. Gd-enhanced MRI and F-18 FDG PET-CT scan demonstrated multiple infiltrations in the cauda equina. During the operation, we removed as many as 11 subdural-extramedullary bean-size lesions involving multiple nerve roots. The paralysis of his left leg recovered rapidly after the operation. During the follow-up period of more than one year, he underwent standard R-CHOP chemical therapy, no evidence of recurrence was noted until the 13th month, the patient died because of intracranial relapse. CONCLUSIONS: Imaging examination is important in the diagnosis of multiple secondary cauda equina non-Hodgkin's lymphoma, and we highlight the significance of gadolinium-enhanced MRI and F-18 FDG-PET/CT in preoperative diagnosis as well as the previous history.

Targeted fascicular biopsy in a patient with prostate cancer.

Patients who present with a history of cancer and the new onset of lumbosacral or peripheral neuropathy should be evaluated for the potential of metastasis. Targeted fascicular biopsy can be useful to diagnose atypical lesions within peripheral nerves in patients with major or progressive neurological deficits. In this video, the authors demonstrate the technique of targeted fascicular biopsy of the sciatic nerve in a 63-year-old man with a history of prostate cancer. The video can be found here: https://youtu.be/PTOX9XxNBDU .

Metastatic squamous cell carcinoma to the superior cervical ganglion mimicking a retropharyngeal lymph node.

BACKGROUND: Metastasis of squamous cell carcinoma (SCC) to the superior cervical ganglion (SCG) has never been reported. Its anatomic location may easily be mistaken for a retropharyngeal lymph node. We present the first case of SCC metastasis to the SCG. METHODS: We report a case of a 69year-old never smoking male, who presented with right retropharyngeal PETCT-avid disease following chemoradiation for squamous cell carcinoma of the tonsil. He was brought to the operating room for resection, intraoperative radiation and reconstruction. RESULTS: Intraoperatively, visualization and frozen section confirmed squamous cell carcinoma located in the superior cervical ganglion. The ganglion was resected, intraoperative radiation was given and the patient was reconstructed with a radial forearm free flap. Postoperatively, the patient displayed features of a Horner's syndrome. CONCLUSIONS: The superior cervical ganglion may be mistaken for a retropharyngeal lymph node. Although extremely rare, these entities may be differentiated on the basis of radiological studies.

Review of periorbital nerve enlargement and biopsy techniques.

Periorbital nerve enlargement commonly indicates perineural invasion of malignancy or inflammatory conditions. This study reviews the role of supraorbital and infraorbital nerve biopsies in patients presenting with radiographic enlargement and to elucidate the surgical technique involved. A retrospective chart review (1997-2014) was performed at a single tertiary center. Patients with radiographic confirmation of enlarged supraorbital/infraorbital nerves that underwent biopsy were included. Charts were reviewed for: patient demographics and history, clinical symptoms and findings, radiographic findings, surgical method, and treatment. Five patients (4 female, 1 male) met inclusion criteria. Average age was 72.4 years (range 36-90). Four patients had history of cutaneous malignancy. All presented with diplopia and/or dysesthesias. Clinical examination confirmed decreased V1 and/or V2 sensation for 4 patients. Imaging revealed enlargement of V1, V2, and/or V3 in all patients. Infraorbital nerve biopsies were performed in 3 patients via transconjunctival fornix-based orbitotomy with subperiosteal dissection along orbital floor followed by unroofing of infraorbital canal. The remaining 2 underwent supraorbital nerve biopsy via sub-brow incision onto superior orbital rim with reflection of periosteum. Biopsies confirmed squamous cell carcinoma(3), mucoepidermoid carcinoma(1), and idiopathic orbital inflammation(1). Three patients initiated treatment in <1 month. One decided to follow-up closer to home, one was lost to follow-up. For patients presenting with enlarged supraorbital/infraorbital nerves, biopsy can rapidly confirm the underlying condition and facilitate early treatment. A sub-brow approach offers direct access to supraorbital nerve while transconjunctival fornix-based anterior orbitotomy with canal unroofing allows access to infraorbital nerve.

Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer.

NF-κB has an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study, we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, and ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreasing overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits Nerve Growth Factor (NGF) mediated, neural-tumor co-culture in vitro invasion, and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

Impact of perineural and lymphovascular invasion on oncological outcomes in rectal cancer treated with neoadjuvant chemoradiotherapy and surgery.

BACKGROUND: The prognostic significance of perineural and/or lymphovascular invasion (PLVI) and its relationship with tumor regression grade (TRG) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT) and surgery. METHODS: A total of 324 patients with LARC were treated with CRT and operated on between January 1992 and June 2007. Tumors were graded using a quantitative 5-grade TRG classification and the presence of PLVI was histologically studied. RESULTS: At a median follow-up of 79.0 months (range 3-250 months), a total of 80 patients (24.7%) relapsed. The observed 5- and 10-year overall survival (OS) was 83.2 and 74.9 %, respectively. The 5- and 10-year disease-free survival (DFS) was 75.1 and 71.4%, respectively. A significant correlation was found between the TRG and survival (log rank, p < 0.001). The 10-year OS was 32.7% for grade 1, 63.8% for grade 2, 75.0% for grade 3, 90.4% for grade 3+, and 96.0%,for grade 4. The 10-year DFS was 31.8% for grade 1, 58.6% for grade 2, 70.4% for grade 3, 88.4% for grade 3+, and 97.1% for grade 4. In patients with PLVI, the TRG had no impact on survival. When excluding patients with PLVI, the TRG was an independent prognostic factor for OS and DFS. CONCLUSIONS: The presence of PLVI is a more powerful prognostic factor than TRG in LARC patients treated with neoadjuvant CRT followed by surgery. PLVI denotes an aggressive phenotype, suggesting that these patients may benefit from adjuvant systemic therapy.

Peripheral neurolymphomatosis with tracheal asphyxia: a case report and literature review.

BACKGROUND: Neurolymphomatosis (NL) is an extremely rare disease and tracheal asphyxia due to NL has not been previously reported. CASE PRESENTATION: A 54-year-old Chinese woman with a history of diffuse large B-cell lymphoma in her first complete remission developed peripheral neuropathy and tracheal asphyxia. Neurolymphomatosis involving the right brachial plexus and the right vagus nerve was demonstrated by PET/CT, but not by MRI. She underwent urgent tracheotomy and impact chemotherapy using rituximab combined with high dose methotrexate and involved field radiotherapy. She achieved a second complete remission. CONCLUSION: PET/CT plays valuable role in differentiating NL from other neuropathies in patients with lymphoma. Complete remission can be achieved in NL due to large B-cell lymphoma.

Prognostic significance of the concomitant existence of lymphovascular and perineural invasion in locally advanced gastric cancer patients who underwent curative gastrectomy and adjuvant chemotherapy.

OBJECTIVE: In this study, we evaluated the prognostic significance of the concomitant existence of lymphovascular invasion and perineural invasion in patients with advanced gastric cancer. METHODS: A total of 206 consecutive patients with Stage II or III gastric cancer who underwent curative D2 gastrectomy and adjuvant chemotherapy from April 2004 to December 2011 were analyzed. Patients were classified into four groups according to the presence (+) or absence (-) of lymphovascular invasion and perineural invasion: lymphovascular invasion-/perineural invasion- (n = 33), lymphovascular invasion+/perineural invasion- (n = 31), lymphovascular invasion-/perineural invasion+ (n = 54) and lymphovascular invasion+/perineural invasion+ (n = 88). RESULTS: A total of 136 patients (66.0%) received 5-fluorouracil plus cisplatin adjuvant chemotherapy and 70 patients (34.0%) received TS-1. During the median follow-up period of 35.18 months, the median disease-free survival times for lymphovascular invasion-/perineural invasion-, lymphovascular invasion+/perineural invasion- and lymphovascular invasion-/perineural invasion+ were not reached at the time of analysis; however, median disease-free survival for lymphovascular invasion+/perineural invasion+ was the worst (36.73 months, P = 0.001). The median overall survival in the four groups was also not reached at the time of analysis; however, median overall survival with lymphovascular invasion+/perineural invasion+ was the poorest (P = 0.002). In a multivariate analysis, lymphovascular invasion+/perineural invasion+ was an independent prognostic factor for both disease-free survival (hazard ratio = 1.940, 95% confidence interval 1.157-3.252, P = 0.012) and overall survival (hazard ratio = 2.973, 95% confidence interval 1.561-5.662, P = 0.001). CONCLUSIONS: The concomitant existence of lymphovascular and perineural invasion has a significant prognostic impact on disease-free survival and overall survival in patients with Stage II or III gastric cancer.

Perineural spread in pelvic malignancies can be an alternate explanation for pelvic bony metastases rather than hematogenous spread. A report of two cases.

We propose that pelvic malignancies can spread to bone and cause bony metastases using nerves as conduits. We reviewed two cases of pelvic malignancy with perineural spread of bladder cancer and prostate cancer. In a patient with prostate cancer, we identified six lesions that were positive on the (11)C-choline PET/CT scan and MRI; in a patient with bladder cancer, we identified two lesions positive on the (18)F-deoxy-glucose PET/CT scan and MRI. We carefully reviewed the imaging studies, and using established sclerotome maps we identified spinal nerves supplying each of eight pelvic bony lesions. All these spinal nerves showed evidence of tumor infiltration with extension toward the affected bones. We theorize that perineural tumor spread may serve as an additional mechanism of pelvic osseous metastases in pelvic malignancies.

[Radiotherapy for Alleviation of Paraparesis due to Leptomeningeal and Cauda Equina Metastasis of HER2-Positive Breast Cancer: A Case Report].

Leptomeningeal metastasis is a rare entity and its diagnosis is often difficult. Moreover, evidence-based therapeutic strategies have not yet been established. A 52-year-old woman presented with high fever and was diagnosed with bacterial meningitis at first examination;although her fever was alleviated, she experienced motor weakness in both of her lower extremities. Ga scintigraphy highlighted the hot-spot areas of the disease in the cranial bone. She was then transferred to our department. Open biopsy of the skull showed metastasis of the cancer. Chest CT results indicated right breast cancer and Gd-DTPA imaging showed obvious enhancement of the pia mater around the conus medullaris and cauda equina. However, cerebrospinal fluid(CSF)cytological examination did not show the presence of any positive cells;consequently, mastectomy was performed in the thoracic surgical department. The severity of paraparesis and pain in her legs increased;however, repeat MRI 1 month later showed no evidence of any change. Therefore, we performed biopsy of the cauda equina and arachnoid lesions. The pathological diagnosis was metastasis of breast cancer with positive human epidermal growth factor receptor 2(HER2)immunological staining. The results of a repeat cytological examination of the CSF during the surgery were negative. Local radiotherapy(25 Gy/5 Fr)as a monotherapy was selected for the patient, because her family did not approve of the combination of radiotherapy and chemotherapy. The severity of both paraparesis and limb pain decreased immediately after the radiotherapy.

A prospective evaluation of the clinical, histologic, and therapeutic variables associated with incidental perineural invasion in cutaneous squamous cell carcinoma.

BACKGROUND: The prognosis and management of incidental perineural invasion (PNI) in patients with cutaneous squamous cell carcinoma (CSCC) has not been well defined. OBJECTIVE: We sought to investigate the clinical, histologic, and treatment characteristics associated with incidental PNI, histologic PNI extending beyond the tumor bulk, in patients with CSCC. METHODS: We conducted a multicenter prospective analysis of patients with CSCC undergoing Mohs micrographic surgery. RESULTS: The incidence of PNI was 4.6% in 753 CSCC cases. PNI was significantly associated with tumors of the head and neck (P = .039), larger tumor diameter (P < .001), presence of clinically palpable lymphadenopathy (P = .012), and recurrent (P < .001) and painful (P < .001) tumors. Further, PNI was significantly associated with poor tumor differentiation (P < .001), greater tumor thickness (P < .001), a greater number of Mohs stages (P < .001), and larger estimated maximum Mohs margin (P < .001) required to clear the tumor. LIMITATIONS: The low numbers of patients demonstrating incidental PNI limits this study. CONCLUSIONS: The association of incidental PNI with clinicopathological indicators of poor prognosis suggests that incidental PNI may serve as a marker to improve the precision in the prognostic assessment of patients with CSCC.

Is T-stage the only significant factor determining the extent of surgery for gallbladder cancer?

BACKGROUND/AIMS: T-stage is currently the only factor determining the extent of surgery of gallbladder cancer (GBCA). We hypothesized that perineural invasion could be another predictive factor determining the extent of surgery because it is very powerful prognostic factor for GBCA. METHODOLOGY: A retrospective analysis was carried out of patients who underwent operation for gallbladder cancer between February 1991 and November 2011. The data were retrospectively analyzed and reviewed and the microscopic findings were checked by a pathologist. RESULT: Simple and extended cholecystectomy was performed in 82 patients during the study period. In univariate analysis, CA 19-9 level, gross type, depth of invasion, lymph node metastasis, distant metastasis, perineural invasion, lymphatic invasion and vascular invasion were associated with survival (P < 0.05). In multivariate analysis, perineural invasion and vascular invasion had an impact on survival (P < 0.05). CONCLUSIONS: T and N stage are powerful prognostic factor for GBCA, but perineural invasion and vascular invasion are also significant prognostic factors. To improve survival radical resection should be considered in early GBCA with perineural and vascular invasion.

Role of glial cell line-derived neurotrophic factor in perineural invasion of pancreatic cancer.

Perineural invasion (PNI) is the initial infiltration of tumor cells into the retroperitoneal nerve plexus and along the nerves. It precludes curative resection, is thought to be the major cause of local recurrence following resection, and is a special metastatic route in pancreatic cancer. Glial cell line-derived neurotrophic factor (GDNF) was recently recognized as a key player in the PNI process. This review covers the most recently published studies on the role of GDNF in pancreatic cancer. We introduce the players in PNI, summarize the distribution of GDNF and its receptors in pancreatic cancer, and discuss the effects and underlying mechanism of GDNF in the PNI process. Finally, we also review some potential inhibitors for GDNF-targeted therapy.

Perineural spread in head and neck malignancies: clinical significance and evaluation with 18F-FDG PET/CT.

Certain tumors of the head and neck use peripheral nerves as a direct conduit for tumor growth away from the primary site by a process known as perineural spread. Perineural spread is associated with decreased survival and a higher risk of local recurrence and metastasis. Radiologists play an important role in the assessment and management of head and neck cancer, and positron emission tomography/computed tomography (PET/CT) with 2-[fluorine 18]fluoro-2-deoxy-d-glucose (FDG) is part of the work-up and follow-up of many affected patients. Awareness of abnormal FDG uptake patterns within the head and neck is fundamental for diagnosing perineural spread. The cranial nerves most commonly affected by perineural spread are the trigeminal and facial nerves. Risk of perineural spread increases with a midface location of the tumor, male gender, increasing tumor size, recurrence after treatment, and poor histologic differentiation. Focal or linear increased FDG uptake along the V2 division of the trigeminal nerve or along the medial surface of the mandible, or asymmetric activity in the masticator space, foramen ovale, or Meckel cave should raise suspicion for perineural spread. If FDG PET/CT findings suggest perineural spread, the radiologist should look at available results of other imaging studies, especially magnetic resonance imaging, to confirm the diagnosis. Knowledge of common FDG PET/CT patterns of neoplastic involvement along the cranial nerves and potential diagnostic pitfalls is of the utmost importance for adequate staging and treatment planning.

Cauda equina syndrome secondary to intradural renal cell carcinoma metastasis haemorrhage.

Intradural renal cell carcinoma (RCC) metastasis is rare. We report a case of an 81-year-old female presenting with acute cauda equina syndrome (CES), secondary to intradural RCC metastasis haemorrhage. To our knowledge this is the first case of CES secondary to acute haemorrhage within an intradural RCC metastasis.

Pulsed radiofrequency treatment within brachial plexus for the management of intractable neoplastic plexopathic pain.

We report on the use of pulsed radiofrequency (RF) within the plexus for the management of intractable pain in three patients with metastatic or invasive plexopathy. The patients were a 38-year-old woman with a history of breast cancer 6 years earlier whose computed tomography (CT) scans revealed a mass lesion at the infraclavicular part of the right brachial plexus, a 68-year-old man diagnosed with advanced lung cancer whose CT scans revealed a bone metastasis in the right humerus invading the axillary region of the right brachial plexus, and a 67-year-old woman diagnosed with advanced lung cancer whose CT scans revealed a bone metastasis in the left humerus invading the axillary region of the left brachial plexus. Ultrasound-guided pulsed RF was performed within the interscalene brachial plexus. During the follow-up period, their intractable pain was moderately controlled.

Intraneural metastasis of gastric carcinoma leads to sciatic nerve palsy.

BACKGROUND: Soft tissue metastases, in particular intraneural metastasis, from any carcinomas seldom occur. To our knowledge, no case of sciatic nerve palsy due to intraneural metastasis of gastric carcinoma is reported in the literature. CASE PRESENTATION: A case is reported of a 82-year old woman with sciatic nerve palsy with intraneural metastasis of gastric carcinoma. Although she had undergone partial gastrectomy with T2b, N0, M0 two years ago and primary site was cured, she developed sciatic nerve palsy from the carcinoma metastasis directly to the nerve. Operative resection and Histological examination revealed poorly differentiated adenocarcinoma, the same as her primary site adenocarcinoma. CONCLUSIONS: Sciatica is usually caused by a herniated disc or spinal canal stenosis. Sciatic nerve palsy may be caused by nondiscogenic etiologies that may be either intrapelvic or extrapelvic. It is important to image the entire course of the nerve to distinguish these etiologies quickly. The longer the nerve compression the less likely a palsy will recover. Surgery is a good intervention that simultaneously obtains a tissue diagnosis and decompresses the nerve.

Surgical treatment of spinal intradural carcinoma metastases.

BACKGROUND: Intradural metastases of nonneurogenic origin represent an extremely rare manifestation of systemic cancer. The respective literature is very scarce. METHODS: We retrospectively evaluated nine patients with intradural metastases treated surgically from March 2006 until today at our department. RESULTS: Four metastases were intramedullary and five intradural extramedullary. Localisation along the spine involved: cervical n = 3, thoracic n = 3, and conus/cauda n = 3. Five patients were female and four male, with a median age of 71 years. Histology showed: breast cancer n = 2, NSCLC (non-small cell lung cancer) n = 2, SCLC (small cell lung cancer) n = 1, colon carcinoma n = 1, malignant skin melanoma n = 1, squamous cell carcinoma of the skin n = 1, and ovarian carcinoma n = 1. Holospinal dissemination in terms of leptomeningeal carcinomatosis according to MRI or positive CSF (cerebrospinal fluid) cytology, respectively, was found in four patients. Gross total resection was achieved in four patients and debulking in five. Results of surgical decompression were: six patients (67%) exhibited immediate improvement of neurological symptoms and/or pain; four of them even improved according to the McCormick Scale score (44%); two patients (22%) were unchanged, and one (11%) exhibited worsening of neurological symptoms after surgery. Median survival time after surgery was 7.3 months. CONCLUSIONS: Intradural metastases are associated with limited survival time. Accordingly, the aim of surgery is strictly palliative. The majority of patients benefit with respect to neurological deficit/pain (67%) independent of the extent of resection. Thus, decompressive surgery is recommended to increase the quality of life.