Diagnosis Of Perineural Invasion Research Articles

Diagnosis of perineural invasion during Mohs micrographic surgery guides clinical decision-making in the management of cutaneous squamous cell carcinoma

Diagnosis of perineural invasion during Mohs micrographic surgery guides clinical decision-making in the management of cutaneous squamous cell carcinoma

A domain knowledge enhanced yield based deep learning classifier identifies perineural invasion in oral cavity squamous cell carcinoma.

Perineural invasion (PNI), a form of local invasion defined as the ability of cancer cells to invade in, around, and through nerves, has a negative prognostic impact in oral cavity squamous cell carcinoma (OCSCC). Unfortunately, the diagnosis of PNI suffers from a significant degree of intra- and interobserver variability. The aim of this pilot study was to develop a deep learning-based human-enhanced tool, termed domain knowledge enhanced yield (Domain-KEY) algorithm, for identifying PNI in digital slides. Hematoxylin and eosin (H&E)-stained whole-slide images (WSIs, n = 85) were obtained from 80 patients with OCSCC. The model structure consisted of two parts to simulate human decision-making skills in diagnostic pathology. To this aim, two semantic segmentation models were constructed (i.e., identification of nerve fibers followed by the diagnosis of PNI). The inferred results were subsequently subjected to post-processing of generated decision rules for diagnostic labeling. Ten H&E-stained WSIs not previously used in the study were read and labeled by the Domain-KEY algorithm. Thereafter, labeling correctness was visually inspected by two independent pathologists. The Domain-KEY algorithm was found to outperform the ResnetV2_50 classifier for the detection of PNI (diagnostic accuracy: 89.01% and 61.94%, respectively). On analyzing WSIs, the algorithm achieved a mean diagnostic accuracy as high as 97.50% versus traditional pathology. The observed accuracy in a validation dataset of 25 WSIs obtained from seven patients with oropharyngeal (cancer of the tongue base, n = 1; tonsil cancer, n = 1; soft palate cancer, n = 1) and hypopharyngeal (cancer of posterior wall, n = 2; pyriform sinus cancer, n = 2) malignancies was 96%. Notably, the algorithm was successfully applied in the analysis of WSIs to shorten the time required to reach a diagnosis. The addition of the hybrid intelligence model decreased the mean time required to reach a diagnosis by 15.0% and 23.7% for the first and second pathologists, respectively. On analyzing digital slides, the tool was effective in supporting human diagnostic thinking. The Domain-KEY algorithm successfully mimicked human decision-making skills and supported expert pathologists in the routine diagnosis of PNI.

Prognostic Value of Perineural Invasion on Survival and Recurrence in Oral Squamous Cell Carcinoma.

A diagnosis of perineural invasion (PNI) is widely accepted as an unfavorable prognostic factor in various solid malignancies. Although PNI has been described as a high-risk parameter in oral squamous cell carcinoma (OSCC), its role in the current staging manuals of the American Joint Committee on Cancer (AJCC) is rather subordinate. We analysed the prognostic value of PNI on survival and recurrence in a large, multicenter OSCC cohort and a population-based approach. A total of 493 OSCC patients with primary tumor resection to negative margins and concomitant neck dissection between 2010 and 2017 were enrolled. PNI was evaluated in relation to overall survival (OAS) and recurrence-free survival (RFS) using uni- and multi-variable Cox regression. The median follow-up time was 5.0 years and PNI was diagnosed in 48 patients (9.7%). A pathohistological verification of PNI correlated significantly with a deteriorated OAS in uni- (HR 2.312; 95% CI 2.312–3.493, p = 0.001) and multivariable Cox regression (HR 1.820; 95% CI 1.164–2.847, p = 0.009). Additionally, a diagnosis of PNI correlated with increased cumulative, as well as distant, metastasis 5-year-recurrence rates (p = 0.027 and p = 0.011, respectively). The application of adjuvant radiotherapy (RT) or radiochemotherapy (RCT) in patients with PNI did not alter OAS or RFS in survival analysis when compared to patients without PNI. The results underline the adverse impact of PNI on the survival and recurrence of surgically treated OSCC patients. Based on our findings, we highly recommend an emphasis on PNI in the TNM staging concept.

The Diagnosis of Perineural Invasion: A Crucial Factor in Novel Algorithm of Coexistence of Conventional and Nerve-Sparing Radical Hysterectomy.

Nerve-sparing radical hysterectomy (NSRH) was introduced to mitigate adverse effects associated with conventional radical hysterectomy (CRH) in cervical cancer. However, the introduction of NSRH was compromised by possible existence of perineural invasion (PNI). Additionally, the coexistence of NSRH and CRH is currently the fact. The aim of the study was to review the literature and attempt to construct a novel and preliminary PNI diagnostic algorithm that would establish the coexistence of NSRH and CRH in one system of early-stage cervical cancer (ESCC) surgical treatment. This algorithm takes into account the PNI risk factors and current and future diagnostic methods such as imaging and biopsy.

A direct transcutaneous approach to infraorbital nerve biopsy

ABSTRACT Purpose To describe a novel transcutaneous infraorbital nerve biopsy technique which can be performed to aid in the diagnosis of perineural invasion (PNI) of facial cutaneous squamous cell carcinoma (SCC). Methods A single-center retrospective chart review was performed. Patients diagnosed with SCC with PNI via an infraorbital nerve biopsy between February 2019 and February 2020 were included. Data collected consisted of patient demographics, medical history, clinical presentation and exam, histologic and radiographic findings, treatment, and outcomes. Results Four patients (3 male, 1 female) met inclusion criteria. The mean age at diagnosis was 79.5 years (range 66–85 years). Three of the four patients had a history of facial skin lesions, including actinic keratosis and SCC, involving the nose, cheek, or ear. One patient had no history of cutaneous malignancy. All patients presented with cranial neuropathies, including total V2 hypoesthesia. The most common presenting symptom was facial pain, followed by diplopia, unilateral facial weakness, and hypoesthesia in the V1 and/or V2 distribution. Transcutaneous infraorbital nerve biopsy in all patients revealed squamous cell carcinoma with no biopsy complications. Conclusion Definitive diagnosis of PNI can be challenging but is important to minimize tumor-related morbidity. Infraorbital nerve biopsy can establish this diagnosis, especially in the context of negative or indeterminate imaging findings. This work comprises the first description of a transcutaneous approach to infraorbital nerve biopsy, which is a minimally invasive technique that can be performed in an outpatient procedure suite with limited to no sedation.

New method for the assessment of perineural invasion from perihilar cholangiocarcinoma.

Perineural invasion (PN) is often found in perihilar cholangiocarcinoma. New procedure was developed to assess PN around the right hepatic artery (RHA) using dual-energy computed tomography (DECT). Thirty patients with perihilar cholangiocarcinoma who underwent DECT before biliary drainage were retrospectively reviewed. Mask images, i.e., the periarterial layer (PAL) around the RHA and superior mesenteric artery (SMA), were made from late arterial phase DECT. The mean CT number of the PAL was measured. Twenty patients with PN around the RHA were classified into the PN (+) group. The remaining 10 patients without PN and other 26 patients with other diseases that are never accompanied with PN were classified into the PN (-) group. The PAL ratio (the CT number of the PAL around the RHA relative to that around the SMA) was calculated. Both the mean CT number of the PAL around the RHA and the PAL ratio were significantly higher in the PN (+) group than in the PN (-) group. According to an ROC analysis, the predictive ability of the PAL ratio was superior. Using the cutoff value of the PAL ratio 1.009, a diagnosis of PN around the RHA was made with approximately 75% accuracy. Assessment with CT number of the PAL reconstructed from DECT images is an easy and objective method to diagnose PN.

Approaches to Perineural, Lymphovascular, and Single-Cell Disease.

Mohs micrographic surgeons should be adept in identifying and managing perineural invasion (PNI), lymphovascular invasion (LVI), and single-cell spread (SCS), features denoting high-risk behavior of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and microcystic adnexal carcinoma (MAC). The purpose of this article is to review the literature and guidelines regarding the diagnosis of PNI, LVI, and SCS in BCC, cSCC, and MAC and examine the role of advanced diagnostic studies, adjuvant therapy, and reconstructive techniques of these high-risk tumors. We performed a literature search including the following terms: PNI, LVI, SCS, BCC, cSCC, keratinocyte carcinoma, MAC, sentinel lymph node biopsy, radiation, chemotherapy, and staging. Relevant studies, case reports, and review articles were included, as well as National Comprehensive Cancer Network guidelines. Pancytokeratin immunohistochemistry may aid in the diagnosis of high-risk features of BCC and cSCC. Reconstruction of the Mohs defect should be carefully considered to allow for thorough inspection. Radiation therapy should be considered as an adjuvant treatment option for high-risk cSCC and BCC. Close surveillance for recurrence is warranted. The Mohs surgeon should be competent in identification of high-risk tumors and to understand how best to manage, further treat, and follow these tumors.

Redefining Perineural Invasion: Integration of Biology With Clinical Outcome

A diagnosis of perineural invasion (PNI), defined as cancer within or surrounding at least 33% of the nerve, leads to selection of aggressive treatment in squamous cell carcinoma (SCC). Recent mechanistic studies show that cancer and nerves interact prior to physical contact. The purpose of this study was to explore cancer-nerve interactions relative to clinical outcome. Biopsy specimens from 71 patients with oral cavity SCC were stained with hematoxylin and eosin and immunohistochemical (IHC; cytokeratin, S100, GAP43, Tuj1) stains. Using current criteria, PNI detection was increased with IHC. Overall survival (OS) tended to be poor for patients with PNI (P = .098). OS was significantly lower for patients with minimum tumor-nerve distance smaller than 5 μm (P = .011). The estimated relative death rate decreased as the nerve-tumor distance increased; there was a gradual drop off in death rate from distance equal to zero that stabilized around 500 μm. In PNI-negative patients, nerve diameter was significantly related to OS (HR 2.88, 95%CI[1.11,7.49]). Among PNI-negative nerves, larger nerve-tumor distance and smaller nerve diameter were significantly related to better OS, even when adjusting for T-stage and age (HR 0.82, 95% CI[0.72,0.92]; HR 1.27, 95% CI[1.00,1.62], respectively). GAP43, a marker for neuronal outgrowth, stained less than Tuj1 in nerves at greater distances from tumor (OR 0.76, 95% CI[0.73,0.79]); more GAP43 staining was associated with PNI. Findings from a small group of patients suggest that nerve parameters other than presence of PNI can influence outcome and that current criteria of PNI need to be re-evaluated to integrate recent biological discoveries.

Management of squamous cell and basal cell carcinomas of the head and neck with perineural invasion.

Perineural invasion (PNI) occurring in non-melanoma skin cancers (NMSC) is associated with an increased risk of locoregional recurrence and reduced disease-free survival. This necessitates early and accurate diagnosis, appropriate risk-stratification and a clear management strategy. The diagnosis of PNI is based on careful clinical assessment, imaging and histopathology. Surgery, preferably with margin control, and definitive or adjuvant radiotherapy (ART) are established treatment strategies for PNI. Clinical uncertainty remains over the role of ART in incidental PNI. This review synthesises current literature to ascertain which clinicopathological features impart a higher risk to individuals with PNI in NMSC, in order to provide treatment algorithms, including the identification of patient subsets that are most likely to benefit from ART. This includes those with extratumoural PNI, involvement of larger-calibre nerves, tumour invasion beyond dermis, recurrent tumour or diffuse intratumoural spread. Patients with clinical PNI may be optimally managed by a multidisciplinary head and neck cancer service that is best placed to offer skull base surgery and intensity-modulated radiation therapy (IMRT). The management options presented are stratified by histological subtype and a new classification of PNI into low-risk, medium-risk and high-risk groups.

Gene Variability between Perineural-Positive and Perineural-Negative Squamous Cell Skin Cancers

Background: Recurrent cutaneous squamous cell cancer (CSCC) is associated with poor outcomes with perineural invasion reported as a frequent finding in such lesions. Given the morbidity associated with late recurrence, identifying aggressive subtypes of CSCC at the time of primary excision is all the more necessary. This project sought to identify differentially expressed genes (DEGs) between perineural invasion-positive (PP) and perineural invasion-negative (PN) CSCC. Gene-based classification models for diagnosis of perineural invasion in CSCC were also developed. Method: Forty fresh-frozen surgical specimens of CSCC with presence or absence of histopathological perineural invasion were processed for RNA isolation and hybridization to Affymetrix-U219 DNA microarrays. Raw gene expression data were normalized by Robust Multi-array Averaging (RMA) and log2 transformed. DEGs were identified by empirical Bayes statistics using the Bioconductor limma package. BRB-ArrayTools software was used to develop gene expression-based sample classification models. Using leave-one-out cross-validation, the resulting accuracies of eight different classification algorithms were evaluated. Results: Twenty-one PP and 19 PN samples were analyzed. At a stringent limma p-value (p<0.001), 24 genes were differentially expressed between specimens. The cross-validated performance of the eight classification models exhibited a mean accuracy of 85-95%. Diagonal linear discriminant was most accurate at 95%, followed by Bayesian compound covariate at 94%. The poorest accuracy (85%) was observed for 1-Nearest neighbor and Support vector machines. For all eight methods, the sensitivities and specificities ranged from 79%-95%. Conclusion: Gene expression distinguishes between PP and PN CSCC. Classification models based on these gene patterns distinguish PP and PN cancers with strong statistical accuracy and may potentiate more timely and objective diagnosis of perineural invasion that could guide more comprehensive adjuvant therapies.

Contralateral Cranial Polyneuropathy Due to Perineural Invasion by a Cutaneous Squamous Cell Carcinoma

Cutaneous malignancies may spread to underlying nerves, a process known as perineural invasion (PNI). We report a patient who was found to have PNI presenting as a cranial polyneuropathy on the contralateral side of the face many years after the resection of a squamous cell carcinoma. All diagnostic testing was unrevealing until nerve biopsy was performed. This emphasizes the long asymptomatic period between treatment of a cutaneous malignancy and detection of PNI, and the development of PNI at a site distant from the original malignancy. Biopsy of a clinically involved nerve may permit diagnosis of PNI when other studies are normal.

Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia II. Perineural invasion

Perineural invasion (PNI) is an important histologic factor that plays a significant role in cutaneous tumors' aggressiveness. We sought to evaluate the incidence, features, and outcomes of cutaneous squamous cell carcinoma with PNI in patients treated with Mohs micrographic surgery (MMS). This prospective, multicenter, case series included all patients in Australia treated with MMS for squamous cell carcinoma with PNI who were monitored by the Skin and Cancer Foundation Australia between 1993 and 2002. The parameters recorded were patient demographics, duration of tumor, site, preoperative tumor size, recurrence before MMS, histologic subtypes, postoperative defect size, and recurrence at 5 years after MMS. Seventy patients were given a diagnosis of PNI. PNI was more common in men (77.1%) and in previously recurrent tumors (P = .04). The moderately and poorly differentiated histologic subtypes were more likely to be associated with PNI (P < .0001). Tumor sizes before excision, postoperative defect sizes, subclinical extension, and mean number of MMS levels were significantly larger in cases with PNI compared with cases without PNI (P < .0001, P < .0001, P = .002, and P < .0001, respectively). Most patients with PNI (52.9%) were treated with adjunctive radiotherapy. In all, 25 patients completed a 5-year follow-up post-MMS, and two of them (8.0%) were given a diagnosis of recurrence. Although PNI is an uncommon feature of cutaneous squamous cell carcinoma, when present, it is associated with larger, more aggressive tumors, and the risk of recurrence is higher. This emphasizes the importance of tumor excision with margin control and long-term patient monitoring.

Atypical ductal hyperplasia and ductal carcinoma in situ of the breast associated with perineural invasion

Perineural invasion is a histologic feature usually diagnostic of invasion in malignancies. In the breast, however, it has been associated with benign lesions such as sclerosing adenosis (SA), complex sclerosing lesion/radial scar (CSL/RS), and ductal carcinoma in situ (DCIS). This article describes perineural invasion associated with atypical ductal hyperplasia (ADH), florid hyperplasia without atypia (FH), and DCIS. All cases with a diagnosis of perineural invasion were selected from a series of 10,000 breast consult cases. Invasive mammary carcinomas were excluded. Fourteen cases of perineural invasion were found and associated with the following diagnoses: ADH (5), DCIS (3), FH (5), and ductal adenoma (1). Nine cases developed in CSL/RS, 4 cases in SA, and 1 case in a previous biopsy site of ductal adenoma; lesions were all less than 3 mm. The glands involving nerves showed cytologic and architectural features of the adjacent ADH, DCIS, and FH. Immunostaining for protein gene product (PGP) 9.5 marked nerves, and smooth muscle actin antibody highlighted the myoepithelial cells around glands. Perineural invasion seen in association with DCIS and ADH, in a background of CSL/RS and SA, may pose difficulty in diagnosis, especially in small biopsy specimens. It should be assessed with care to avoid misinter-pretation as invasive mammary carcinoma. HUM PATHOL 32:785-790. Copyright © 2001 by W.B. Saunders Company