Predicting intracranial involvement: Unveiling perineural spread in COVID-19-associated mucormycosis, a novel phenomenon.

This study aimed to investigate the risk factors associated with intracranial involvement in COVID-19-associated mucormycosis (CAM) and to develop a nomogram model for predicting the risk of intracranial involvement, with a specific focus on perineural spread. An ambispective analysis was conducted on 275 CAM patients who received comprehensive treatment. Univariable and multivariable logistic regression analyses were performed to identify independent risk factors, and a nomogram was created based on the results of the multivariable analysis. The performance of the nomogram was evaluated using a receiver operating characteristic (ROC) curve, and the discriminatory capacity was assessed using the area under the curve (AUC). The model's calibration was assessed through a calibration curve and the Hosmer Lemeshow test. In the results, the multivariable logistic regression analysis revealed that age (OR: 1.23, 95% CI 1.06-3.79), HbA1c (OR: 7.168, 95% CI 1.724-25.788), perineural spread (OR: 6.3, 95% CI 1.281-19.874), and the disease stage were independent risk factors for intracranial involvement in CAM. The developed nomogram demonstrated good discriminative capacity with an AUC of 0.821 (95% CI 0.713-0.909) as indicated by the ROC curve. The calibration curve showed that the nomogram was well-calibrated, and the Hosmer Lemeshow test yielded a P-value of 0.992, indicating a good fit for the model. In conclusion, this study found that CAM particularly exhibits perineural spread, which is a predictive factor for intracranial involvement. A nomogram model incorporating age, HbA1c, disease stage, and perineural spread was successfully developed for predicting intracranial involvement in CAM patients in both in-patient and out-patient settings.

Discovery of perineural spread in COVID-19-associated mucormycosis reveals a new predictive model for intracranial complications which is crucial for early intervention.

Durable tumor regression and restoration of neurologic function after treatment with anti-PD-1 in patients with functionally unresectable cutaneous squamous cell carcinoma with perineural spread into the cavernous sinus.

PURPOSE: To describe tumor response and cranial nerve function outcomes after administration of anti-PD-1 to patients with cutaneous squamous cell carcinoma (CSCC) with perineural spread to cranial nerves (CN) extending into the cavernous sinus. METHODS: Electronic patient records from a single institution were queried for patients with CSCC of the head and neck causing diplopia (ICD-10 H53.2) who were treated with anti-PD-1. Data extracted included demographics, duration of anti-PD-1 therapy, immune-mediated adverse reactions, tumor response per adapted RECIST v1.1, and changes in CN function and symptoms (e.g., pain). All patients were prescribed cemiplimab 350 mg IV q3 weeks. RESULTS: Four patients met inclusion criteria. They had varying degrees of pain and sensory deficits in branches of the trigeminal nerve (CN V). One, 2, 3 and 1 patients had baseline involvement of CN III, IV, VI and VII, respectively. MRI confirmed perineural cavernous sinus involvement in all patients. Duration of anti-PD-1 therapy ranged 15-60 weeks. All patients experienced an objective anti-tumor response to anti-PD-1; partial response n = 2, complete response n = 2. At a median follow-up of 22 months, responses were ongoing in all patients. All patients demonstrated improvement in ocular motility deficits and pain with resolution of symptoms in 3 and 1 patients, respectively. CONCLUSION: Administration of anti-PD-1 to patients with CSCC with perineural spread into the cavernous sinus can generate durable anti-tumor regressions and restore CN function, while sparing the morbidity associated with surgical resection and/or radiotherapy. Our findings add to emerging literature supporting this treatment approach for this patient population.

An unusual case of a grade I meningioma with perineural spread.

A 39-year-old lady with worsening intermittent diplopia and headaches was diagnosed with a WHO Grade I Meningothelial Meningioma with highly unusual perineural spread on imaging, making this the first reported case of this behaviour. Complete surgical resection was deemed too great a risk and the patient remains under observation. The process of perineural spread is not restricted to more aggressive brain tumours.

Frequency and imaging features of the adjacent osseous changes of salivary gland carcinomas in the head and neck region.

PURPOSE: The association between salivary gland carcinomas and adjacent osseous changes in the head and neck region is not clear. We evaluated the frequency and imaging features of such changes and investigated the specific characteristics of salivary gland carcinomas associated with them. METHODS: A total of 118 patients with histologically proven salivary gland carcinomas were retrospectively reviewed. The imaging characteristics of osseous changes were sorted into three categories based on computed tomography images: sclerotic change, erosive change, and lytic change. The frequency of all these osseous changes and any one of them was compared between different pathologies using Fisher's exact test. Odds ratios were calculated to evaluate the association between these changes and perineural spread. RESULTS: Osseous changes were found in 21 (18%) of 118 cases. Among these, seven (6%) cases were with sclerotic, nine (8%) with erosive, and nine (8%) with lytic changes (four with mixed change). Adenoid cystic carcinoma showed a significantly higher frequency of sclerotic and erosive changes, and either osseous change, than the other salivary gland carcinomas (p < 0.001 for each). Sclerotic changes were only present in the adenoid cystic carcinomas. Perineural spread was a significant factor in showing higher osseous change frequencies (odds ratio = 3.98, p = 0.006). CONCLUSION: Among salivary gland carcinomas in the head and neck region, adenoid cystic carcinomas had a significantly higher frequency of adjacent osseous changes, especially sclerotic changes, than other salivary gland carcinomas.

A novel mechanism for the formation and propagation of neural tumors and lesions through neural highways.

By recognizing anatomic and radiologic patterns of rare and often misdiagnosed peripheral nerve tumors/lesions, we have defined mechanisms for the propagation of neural diseases. The novel concept of the nervous system serving as a complex system of "highways" driving the neural and perineural spread of these lesions is described in three examples: Intraneural dissection of joint fluid in intraneural ganglion cysts, perineural spread of cancer cells, and dissemination of unknown concentrations of neurotrophic/inhibitory factors for growth in hamartomas/choristomas of nerve. Further mapping of these pathways to identify the natural history of diseases, the spectrum of disease evolution, the role of genetic mutations, and how these neural pathways interface with the lymphatic, vascular, and cerebrospinal systems may lead to advances in targeted treatments.

Circumdural extension of perineural spread leading to bilateral disease in neurolymphomatosis.

INTRODUCTION: Patients with neurolymphomatosis (NL) often present with one primarily symptomatic limb but can be found to have bilateral upper or bilateral lower limb disease during workup. We sought to explain the finding of bilateral disease and understand if there was a connection to the initial, symptomatic side of disease. METHODS: We reviewed imaging studies of patients with bilateral upper or bilateral lower limb disease from a previously published cohort from our institution, as well as more recent patients seen at our institution. We reviewed demographics (sex and age), clinical data (primary or secondary disease and biopsy-proven diagnosis), and imaging findings (primary involved nerve, contralateral nerve(s) affected, and location of circumdural extension). RESULTS: We identified 8 cases with evidence of bilateral disease out of 22 cases of tumefactive NL. All eight cases were found to have circumdural extension of disease to the corresponding contralateral nerve. CONCLUSION: We describe the pathomechanism of spread in our cases of bilateral upper or bilateral lower limb disease, where NL spreads along a dominant nerve toward the spinal canal and moves circumdurally to affect the corresponding contralateral nerve. We believe this information is useful to further understand the spread of NL, as well as offering important diagnostic and prognostic information for patients.

Perineural spread to the brachial plexus: a focused review of proposed mechanisms and described pathologies.

BACKGROUND: Perineural spread (PNS) is an emerging mechanism for progressive, non-traumatic brachial plexopathy. We aim to summarize the pathologies (tumor and infection) shown to have spread along or to the brachial plexus, and identify the proposed mechanisms of perineural spread. METHODS: A focused review of the literature was performed pertaining to pathologies with identified perineural spread to the brachial plexus. RESULTS: We summarized pathologies currently reported to have PNS in the brachial plexus and offer a structure for understanding and describing these pathologies with respect to their interaction with the peripheral nervous system. CONCLUSIONS: Perineural spread is an underrepresented entity in the literature, especially regarding the brachial plexus. It can occur via a primary or secondary mechanism based on the anatomy, and understanding this mechanism helps to support biopsies of sacrificial nerve contributions, leading to more effective and timely treatment plans for patients.

Radiographic review of anatomy and pathology of the masticator space: what the emergency radiologist needs to know.

The differential diagnosis of a masticator space (MS) lesion is broad, owing in part to the multiple structures contained within such a small region. It is also because the MS is adjacent to many of the other deep spaces within the head and neck, which can act as gateways for disease spread. Therefore, emergency radiologists must be familiar with anatomy of the MS, as well as adjacent spaces in order to provide an accurate diagnosis to the referring clinician. This article illustrates the anatomy and common pathologies within the MS using a case-based multimodality approach. Common masticator space pathologies can be categorized into inflammatory/infectious, neoplastic, and vasoformative lesions. Important imaging features of MS lesions and patterns of disease spread will be discussed, with the aim of making this complex deep space more approachable in the emergent setting.

Facial nerve tractography: A new tool for the detection of perineural spread in parotid cancers.

OBJECTIVES: To determine whether facial nerve MR tractography is useful in detecting PeriNeural Spread in parotid cancers. METHODS: Forty-five participants were enrolled. Thirty patients with surgically managed parotid tumors (15 malignant, 15 benign) were compared with 15 healthy volunteers. All of them had undergone 3T-MRI with diffusion acquisition and post-processing constrained spherical deconvolution-based tractography. Parameters of diffusion-weighted sequences were b-value 1,000 s/mm2, 32 directions. Two radiologists performed a blinded visual reading of tractographic maps and graded the facial nerve average pathlength and fractional anisotropy (FA). We also compared diagnostic accuracy of tractography with morphological MRI sequences to detect PeriNeural Spread. Non-parametric methods were used. RESULTS: Average pathlength was significantly higher in cases with PeriNeural Spread (39.86 mm [Quartile1: 36.27; Quartile3: 51.19]) versus cases without (16.23 mm [12.90; 24.90]), p<0.001. The threshold above which there was a significant association with PeriNeural Spread was set at 27.36 mm (Se: 100%; Sp: 84%; AUC: 0.96, 95% CI 0.904-1). There were no significant differences in FA between groups. Tractography map visual analyses directly displayed PeriNeural Spread in distal neural ramifications with sensitivity of 75%, versus 50% using morphological sequences. CONCLUSIONS: Tractography could be used to identify facial nerve PeriNeural Spread by parotid cancers. KEY POINTS: • Tractography could detect facial nerve PeriNeural Spread in parotid cancers. • The average pathlength parameter is increased in case of PeriNeural Spread. • Tractography could map PeriNeural Spread more precisely than conventional imaging.

Diagnostic and prognostic value of 18F-FDG PET, CT, and MRI in perineural spread of head and neck malignancies.

OBJECTIVES: We assessed whether quantitative imaging biomarkers derived from fluorodeoxyglucose-positron emission tomography (18F-FDG PET) could be extracted from perineural spread (PNS) in head and neck malignancies (HNM) to improve patient risk stratification. METHODS: A case-control exploratory study (1:2 ratio) enrolled 81 patients with FDG-avid HNM. The case-group comprised 28 patients with documented PNS (reference: expert consensus), including 14 squamous cell carcinomas (SCC). Imaging biomarkers were extracted from the PNS on 18F-FDG PET, CT-scan, and MRI. The control-group enrolled 53 SCCs. The Cox proportional-hazards regression model explored the association with overall survival by univariate and multivariate analyses. RESULTS: The rate of PNS detection by 18F-FDG PET was 100% in the case-group. Quantitative imaging biomarkers were not associated with the presence of sensory (p>0.20) or motor (p>0.10) symptoms. In SCC patients (case: 14; control: 53), PNS was associated with a hazard ratio of death of 5.5 (95%CI: 1.4:20.9) by multivariate analysis. Increased cranial nerve SUVmax was significantly associated with poorer overall survival by univariate analysis (p=0.001). CONCLUSIONS: Our pilot study showed the feasibility of extracting 18F-FDG PET biomarkers from PNS in FDG-avid HNM. Our results encourage the development of new PET/CT- or PET/MRI-guided management strategies in further prospective studies. KEY POINTS: • 18F-FDG PET/CT detects PNS in FDG-avid HNM. • PNS metabolism is more heterogeneous than healthy tissue. • PNS diagnosis is crucial: most patients were asymptomatic, N0 and M0. • PNS diagnosis is associated with poorer overall survival in SCC. • PET/CT- or PET/MRI-guided management strategies should be evaluated.

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 .

Mathematical model of perineural tumor spread: a pilot study.

BACKGROUND: Perineural spread (PNS) of pelvic cancer along the lumbosacral plexus is an emerging explanation for neoplastic lumbosacral plexopathy (nLSP) and an underestimated source of patient morbidity and mortality. Despite the increased incidence of PNS, these patients are often times a clinical conundrum-to diagnose and to treat. Building on previous results in modeling glioblastoma multiforme (GBM), we present a mathematical model for predicting the course and extent of the PNS of recurrent tumors. METHODS: We created three-dimensional models of perineurally spreading tumor along the lumbosacral plexus from consecutive magnetic resonance imaging scans of two patients (one each with prostate cancer and cervical cancer). We adapted and applied a previously reported mathematical model of GBM to progression of tumor growth along the nerves on an anatomical model obtained from a healthy subject. RESULTS: We were able to successfully model and visualize perineurally spreading pelvic cancer in two patients; average growth rates were 60.7 mm/year for subject 1 and 129 mm/year for subject 2. The model correlated well with extent of PNS on MRI scans at given time points. CONCLUSIONS: This is the first attempt to model perineural tumor spread and we believe that it provides a glimpse into the future of disease progression monitoring. Every tumor and every patient are different, and the possibility to report treatment response using a unified scale-as "days gained"-will be a necessity in the era of individualized medicine. We hope our work will serve as a springboard for future connections between mathematics and medicine.

Squamous cell carcinoma presenting with trigeminal anesthesia: An uncommon presentation of head & neck cancer with unknown primary.

BACKGROUND: The differential diagnosis of facial anesthesia is vast. This may be secondary to trauma, neoplasm, both intracranial and extracranial, infection, and neurologic disease. When evaluating a patient with isolated facial anesthesia, the head and neck surgeon often thinks of adenoid cystic carcinoma, which has a propensity for perineural invasion and spread. When one thinks of head and neck squamous cell carcinoma with or without unknown primary, the typical presentation involves dysphagia, odynophagia, weight loss, hoarseness, or more commonly, a neck mass. Squamous cell carcinoma presenting as facial anesthesia and perineural spread, with no primary site is quite rare. METHODS: Case presentations and review of the literature. CONCLUSIONS: Trigeminal anesthesia is an uncommon presentation of head and neck squamous cell carcinoma with unknown primary. We present two interesting cases of invasive squamous cell carcinoma of the trigeminal nerve, with no primary site identified. We will also review the literature of head and neck malignancies with perineural spread and the management techniques for the two different cases presented.

Perineural spread-susceptible structures: a non-pathological evaluation of the skull base.

Perineural spread adenoid cystic carcinoma can alter the dimension of foramina and canals of the skull base. The objective of this study was to determine the range of normal variation of the foramina and canals of both hemicranium. We analyzed 200 individuals with no alterations of the skull base in a retrospective manner using high-resolution computed tomography. We measured the short and long axis diameters of the foramen rotundum (FR), foramen ovale (FO), stylomastoid foramen (SMF), pterygoid canal (PTC), internal auditory canal (IAC), and the facial nerve canal in its labyrinthine portion (LPFC) to calculate the area in each hemicranium, compare them and obtain the normal range of asymmetry. Parametric and non-parametric comparison tests were realized. The structures that had the lowest range of asymmetry were the LPFC (0.00-0.79 mm2) and the FR (0.00-2.12 mm2). The one that had the highest asymmetry range was the FO (0.00-9.16 mm2). Significant differences were found in the FO (p = 0.01) and the IAC (p = 0.00) in the gender comparison. We determined a normal asymmetry range of the susceptible foramina and canals of the skull base. This study reports a useful and objective measure to differentiate anatomical from pathological variations of the foramina and canals of the skull base by age and gender. Our results establish a basis for future studies that evaluate this range as a diagnostic tool of metastasis in the skull base as a complement of other imaging techniques.

Diagnostic Challenge: Sequential Unilateral Cranial Neuropathies Due to Perineural Spread of Carcinoma.

An 86-year old man developed sequential dysfunction of trigeminal (V1), facial, abducens, trigeminal (v2), oculomotor, and hypoglossal cranial nerves on the right over 20 months. Magnetic resonance imaging (MRI) showed a lesion in the right cavernous sinus. Although there was clinical suspicion that this was related to perineural spread of an extracranial tumour, a primary lesion was not discovered. Stereotactic biopsies of the intracranial lesion were non-diagnostic, and the patient succumbed to his tumour following a period of rapid growth. Postmortem examination showed the intracranial lesion to be a carcinoma with squamous features. This case highlights the challenges of diagnosis of intracranial perineural spread and the potential for transformation from indolent to aggressive tumour behaviour.

Galectin-1 is associated with poor prognosis in patients with cutaneous head and neck cancer with perineural spread.

Spread of head and neck cancer along the cranial nerves is often a lethal complication of this tumour. Current treatment options include surgical resection and/or radiotherapy, but recurrence is a frequent event suggesting that our understanding of this tumour and its microenvironment is incomplete. In this study, we have analysed the nature of the perineural tumour microenvironment by immunohistochemistry with particular focus on immune cells and molecules, which might impair anti-tumour immunity. Moderate to marked lymphocyte infiltrates were present in 58.8% of the patient cohort including T cells, B cells and FoxP3-expressing T cells. While human leukocyte antigen (HLA) class I and more variably HLA class II were expressed on the tumour cells, this did not associate with patient survival or recurrence. In contrast, galectin-1 staining within lymphocyte areas of the tumour was significantly associated with a poorer patient outcome. Given the known role of galectin-1 in immune suppression, the data suggest that galectin inhibitors might improve the prognosis of patients with perineural spread of cancer.

Ultrasonography of sciatic nerve endometriosis.

INTRODUCTION: We describe the ultrasonographic findings of sciatic nerve endometriosis. METHODS: Two premenopausal women with catamenial sciatica symptoms were examined, the first without a history of endometriosis, the second with previously confirmed endometriosis of the ovary. Ultrasonography, extending from the sciatic notch to the level of the ischial tuberosity showed that the sciatic nerve was "engulfed" in a large, perineural, hypoechogenic, inhomogeneous lesion with an irregular contour corresponding to an endometrioma. The nerve was enlarged, but it was discernible within the lesion, except at its most cranial part. MRI of the pelvis showed intrapelvic extension in both patients. RESULTS: The first patient was treated with a gonadotropin-releasing hormone agonist, leading to complete morphological regression and normalization of nerve structure, parallel with symptomatic resolution. CONCLUSIONS: These cases illustrate that ultrasound is a feasible imaging modality for sciatic nerve endometriosis that may even be used to monitor morphological regression of endometrial tissue during treatment. Muscle Nerve 54: 500-505, 2016.

Perineural spread of pelvic malignancies to the lumbosacral plexus and beyond: clinical and imaging patterns.

OBJECT Perineural spread along pelvic autonomie nerves has emerged as a logical, anatomical explanation for selected cases of neoplastic lumbosacral plexopathy (LSP) in patients with prostate, bladder, rectal, and cervical cancer. The authors wondered whether common radiological and clinical patterns shared by various types of pelvic cancer exist. METHODS The authors retrospectively reviewed their institutional series of 17 cases concluded as perineural tumor spread. All available history, physical examination, electrodiagnostic studies, biopsy data and imaging studies, evidence of other metastatic disease, and follow-up were recorded in detail. The series was divided into 2 groups: cases with neoplastic lumbosacral plexopathy confirmed by biopsy (Group A) and cases included based on imaging characteristics despite the lack of biopsy or negative biopsy results (Group B). RESULTS Group A comprised 10 patients (mean age 69 years); 9 patients were symptomatic and 1 was asymptomatic. The L5-S1 spinal nerves and sciatic nerve were most frequently involved. Three patients had intradural extension. Seven patients were alive at last follow-up. Group B consisted of 7 patients (mean age 64 years); 4 patients were symptomatic, 2 were asymptomatic, and 1 had only imaging available. The L5-S1 spinal nerves and the sciatic nerve were most frequently involved. No patients had intradural extension. Four patients were alive at last follow-up. CONCLUSIONS The authors provide a unifying theory to explain lumbosacral plexopathy in select cases of various pelvic neoplasms. The tumor cells can use splanchnic nerves as conduits and spread from the end organ to the lumbosacral plexus. Tumor can continue to spread along osseous and muscle nerve branches, resulting in muscle and bone "metastases." Radiological studies show a reproducible, although nonspecific pattern, and the same applies to clinical presentation.

Recurrent rectal cancer causing lumbosacral plexopathy with perineural spread to the spinal nerves and the sciatic nerve: an anatomic explanation.

Several groups have reported cases of rectal cancer with carcinomatous involvement of the lumbosacral plexus and sciatic, obturator, pudendal, or spinal nerves. To our best knowledge, clear examples of perineural tumor spread in rectal carcinoma have not yet been described. We retrospectively reviewed clinical data and imaging studies of three patients with primary or recurrent rectal cancer involving the lumbosacral plexus. Imaging studies included MRI and (18)FDG PET/CT scans in all (n = 3) patients, histological samples were available in two (n = 2). Imaging studies demonstrated distinct features of tumor spread from the organ to the plexus and beyond in all cases (n = 3), histological specimens demonstrated perineural involvement thus supporting our theory (n = 2). We present these three cases of perineural tumor spread in rectal cancer as a proof of concept. We hypothesize that not only our cases, but other similar reported cases can be explained anatomically by extension of the rectal cancer to the inferior hypogastric plexus with perineural tumor spread to the lumbosacral plexus using the pelvic and sacral splanchnic nerves as conduits. Once the tumor reaches the lumbosacral plexus, it can continue to spread proximally or distally. We believe that perineural spread of colon cancer represents an important, under-recognized mechanism of recurrence to neighboring major nerves in the pelvis.

Assessment of perineural spread in advanced cutaneous squamous cell carcinomas treated with immunotherapy.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) has a propensity for perineural spread (PNS) which is associated with poorer treatment outcomes. Immunotherapy is the new standard of care treatment for advanced CSCC resulting in durable responses. PNS is not captured by traditional response assessment criteria used in clinical trials, e.g. RECIST 1.1, and there is limited literature documenting radiological PNS responses to immunotherapy. In this study we assess PNS responses to immunotherapy using a modified grading system. METHODS: This is an Australian single-center retrospective review of patients with advanced CSCC who were treated with immunotherapy between April 2018 and February 2022 who had evidence of PNS on pre-treatment magnetic-resonance imaging (MRI). The primary outcome was blinded overall radiological response in PNS using graded radiological criteria, post-commencement of immunotherapy. Three defined timepoints (< 5 months, 5-10 months, > 10 months) were reviewed. Secondary outcomes included a correlation between RECIST 1.1 and PNS assessments and the assessment of PNS on fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT). RESULTS: Twenty CSCC patients treated with immunotherapy were identified. Median age was 75.7 years and 75% (n = 15) were male. All patients had locoregionally advanced disease and no distant metastases. Median follow-up was 18.5 months (range: 2-59). 70% (n = 14) demonstrated a PNS response by 5 months. Three patients experienced pseudoprogression. One patient had PNS progression by the end of study follow up. RECIST 1.1 and PNS responses were largely concordant at > 10 months (Cohen's Kappa 0.62). 5/14 cases had features suspicious for PNS on FDG-PET/CT. CONCLUSIONS: PNS response to immunotherapy can be documented on MRI using graded radiological criteria. High response rates were seen in PNS with the use of immunotherapy in this cohort and these responses were largely concordant with RECIST 1.1 assessments. FDG-PET/CT demonstrated limited sensitivity in the detection of PNS.