Microscopic Perineural Invasion Research Articles

Non-Melanomatous Skin Cancers of the Head and Neck with Perineural Invasion: A 50-Year Single-Institution Experience

<h3>Purpose/Objective(s)</h3> The aim of this study was to evaluate patient outcomes and practice patterns among patients treated for non-melanomatous skin cancers of the head and neck with microscopic or clinical perineural invasion (PNI) using radiotherapy (RT) at a single institution. <h3>Materials/Methods</h3> To determine severe (grade 3+) toxicity and clinical outcomes, we reviewed the medical records of 283 patients who received primary RT or postoperative RT +/- chemotherapy between 1965 and 2019 for non-melanomatous skin cancers of the head and neck with PNI. Modalities included orthovoltage photons, megavoltage photons, and en face electrons with either daily (QD) or twice-daily (BID) fractionation. Field extent of the primary site was either local (2 cm margin), extended (>2 cm margin), or to the base of skull (BOS). <h3>Results</h3> The median age at the start of RT was 64 years old. Overall, 154 patients had microscopic PNI and 129 had clinical PNI. The median BID dose was 74.4 Gy (range, 32 – 79.2 Gy) and the median QD dose was 64 Gy (range, 15 – 79.5 Gy). Field extent was 25% local, 38% extended, and 37% BOS. Nodal involvement was seen in 17% of patients. Elective nodal irradiation was performed in 51% of node-negative patients. For patients with microscopic PNI, the 5- and 10-year rates of local control, local-regional control, disease-free survival, cause-specific survival, and overall survival were 85% and 80%, 78% and 74%, 76% and 72%, 80% and 79%, and 59% and 40%, respectively. For patients with clinical PNI, the 5- and 10-year rates of local control, local-regional control, disease-free survival, cause-specific survival, and overall survival were 59% and 57%, 57% and 55%, 54% and 52%, 68% and 58%, and 54% and 34%, respectively. In those with clinical PNI, T stage was associated with a statistically significant effect on local control and cause-specific survival on multivariable analysis (p = 0.01 and p = 0.03, respectively). Toxicities of grade 3 or higher occurred at rates of 12% in patients with microscopic PNI and 32% in those with clinical PNI. <h3>Conclusion</h3> Radiation therapy provides good long-term control rates in patients with microscopic PNI and patients with clinical PNI; nevertheless, clinical PNI remains a poor prognostic factor.

Prognostic Impact of Lymphocyte-to-C-Reactive Protein Ratio in Patients Who Underwent Surgical Resection for Pancreatic Cancer.

Increasing evidence indicates that increased systemic inflammation is correlated with poorer cancer-specific survival in various cancer types. This study aimed to evaluate the prognostic value of various combinations of inflammatory factors in patients who underwent surgical resection for pancreatic cancer (PC). We retrospectively analyzed 97 consecutive patients with PC who underwent pancreatectomy. We assessed the predictive impact for recurrence using a combination of 5 inflammatory markers and focused on the lymphocyte-C-reactive protein ratio (LCR) to elucidate its prognostic and predictive value for recurrence-free survival (RFS) and overall survival (OS) in univariate and multivariate analyses using the Cox proportional hazards model. Low preoperative LCR was correlated with low serum hemoglobin, low serum albumin concentration, high frequency of microscopic vascular invasion, and high frequency of microscopic perineural invasion. The low LCR group had significantly worse RFS and OS. Lower preoperative LCR was an independent predictor of shorter RFS and OS in this cohort. Preoperative LCR is a novel and convenient prognostic marker for patients with PC. Patients with low LCR may require more favorable intensive therapy.

Clinical characteristics and treatment outcome of adenoid cystic carcinoma in the external auditory canal

BackgroundThis study reviewed the clinical manifestations, pathological findings, and treatment outcomes of adenoid cystic carcinoma (ACC) in the external auditory canal (EAC). MethodsThis was a retrospective review of 12 patients with a diagnosis of ACC in the EAC seen in a single institution over a 30-year period. Data on the demographics, clinical presentation, treatment strategy, and outcome, as well as the pathological features of ACC, were reviewed and analyzed. ResultsThe male-to-female ratio was 1:3 and the mean patient age was 55.9 years. The most common clinical presentation was otalgia (75%). Ten patients underwent surgical interventions, including radical mastoidectomy in five patients, wide excision in three, and lateral temporal bone resection in two. Adjuvant radiotherapy or concurrent chemoradiotherapy (CCRT) was performed in case of incomplete resection. Two patients underwent non-surgical treatments: radiotherapy in one and CCRT in the other. Microscopic perineural invasion was not associated with otalgia or histological subtype. The mean follow-up period was 84.6 months. Local recurrence occurred in 33% of patients. One-quarter of patients had distant metastasis, and all had lung metastasis. The 5-year overall survival rate for these patients was 82.5%. ConclusionEAC ACC should be included in the differential diagnosis when a patient presents with otalgia and a mass in EAC for more than 6 months, particularly if the patient is a middle-aged female. Otalgia might not be associated with perineural invasion or histological subtype. The lung is the most common site of distant metastasis in patients with EAC ACC. Further studies should determine the optimal treatment protocol for this rare malignancy.

Uncertainties in the choice of dose and elective volumes during postoperative radiotherapy for cutaneous squamous cell carcinoma with perineural invasion.

Introduction: Post operative radiotherapy (PORT) for resected cutaneous squamous cell carcinoma (CSCC) with perineural invasion (PNI) is controversial. Therefore, we conducted a survey to study the patterns of practice and determine whether there is a consensus among Radiation Oncologists (ROs) regarding prescribed dose to the post-operative bed and elective treatment of lymph nodal regions and neural pathways. We also compared the recommendations of the ROs with the 2010 NCCN guidelines. Materials &amp; Methods: In March 2011, we contacted all ROs and trainees residing in the USA through their email address listed in the 2009 ASTRO membership directory. Our survey contained clinical vignettes involving Mohs micrographically resected CSCC with microscopic PNI (mPNI) or clinical (symptomatic or radiographic) cPNI, including named nerve PNI (nPNI). For each vignette, physicians indicated if PORT was appropriate and further specified the dose and volume to treat at standard fractionation. Chemotherapy was not allowed. Responses were stratified according to years of post residency experience, special interest in treating head and neck cancers and number of cases treated per year. We defined consensus as 80% concordance. Results: Three hundred and fifty two responses were completed and analyzed. Approximately 95% recommended PORT for cPNI whereas a mean of 59% recommended PORT for mPNI. There was no consensus regarding dose to the operative bed. Approximately 30% of respondents prescribed 54 Gy or less at standard fractionation, while the NCCN guidelines recommend 60 Gy in 30 fractions. Only 24% were willing to prescribe 66Gy or more in cases of radiographically identified gross residual disease. In cases of mPNI, there was a consensus not to treat elective nodal volumes; on average only 14% treated elective nodal regions. Even in the presence of cPNI, only 40% recommended elective nodal irradiation (ENI). ROs with over ten years’ experience were more willing to offer ENI for cPNI than less experienced ROs (43% vs. 25% p=0.004). For mPNI, there was no consensus for elective neural pathway irradiation (ENP); whereas for cPNI a clear consensus emerged with over 90% recommending ENP. The NCCN guidelines do not have specific recommendations for ENI or ENP. Stratification based on years of post residency experience (&amp;lt;10 vs. 10+ yrs), number of cases treated per year (0-7 vs. 8+ cases per year) and special interest in treating head and neck cancers did not yield any other statistically significant differences. Conclusions: Our data from 2011 demonstrates a lack of consensus among ROs regarding radiation dose to the post-operative bed and designation of elective targets (i.e. nodal regions and neural pathways) for resected CSCC with PNI. In contrast to the NCCN guidelines, nearly 30% of ROs under-dosed the post-operative bed. Majority of ROs omitted elective nodal irradiation even in cases of cPNI. While there was a consensus to treat ENP for cPNI, there was wide variability for treating ENP for mPNI. Since this survey was conducted, several guidelines have been published to educate radiation oncologists regarding electively targeting the neural pathways. Updated More data to evaluate the impact of these guidelines is needed in this setting to guide ROs and achieve homogenous practice patterns.

Recurrence after neoadjuvant therapy and resection of borderline resectable and locally advanced pancreatic cancer

IntroductionThe incidence, timing, and implications of recurrence in patients who underwent neoadjuvant treatment and surgical resection of borderline resectable (BRPC) or locally advanced (LAPC) pancreatic cancer are not well established. Materials and methodsPatients with BRPC/LAPC who underwent post-neoadjuvant resection between 2007 and 2015 were included. Associations between clinicopathologic characteristics and specific recurrence locations, recurrence-free survival (RFS), and overall survival from resection (OS) were assessed using Cox regression analyses. ResultsFor 231 included patients, median survival from diagnosis and resection were 28.0 and 19.8 months, respectively. After a median RFS of 7.9 months, 189 (81.8%) patients had recurred. Multiple-site (n = 87, 46.0%) and liver-only recurrence (n = 28, 14.8%) generally occurred earlier and resulted in significantly worse OS when compared to local-only (n = 52, 27.5%) or lung-only recurrence (n = 18, 9.5%). Microscopic perineural invasion, yN1-yN2 status and elevated pre-surgery CA 19-9 >100 U/mL were associated with both local-only and multiple-site/liver-only recurrence. R1-margin was associated with local-only recurrence (HR 2.03). yN1-yN2 status and microscopic perineural invasion were independent predictors for both poor RFS and OS, while yT3-yT4 tumor stage (HR 1.39) and poor tumor differentiation (HR 1.60) were only predictive of poor OS. Adjuvant therapy was independently associated with both prolonged RFS (HR 0.73; median 7.0 vs. 10.9 months) and OS (HR 0.69; median 15.4 vs. 22.7 months). ConclusionDespite neoadjuvant therapy leading to resection and relatively favorable pathologic tumor characteristics in BRPC/LAPC patients, more than 80% of patients experienced disease recurrence, 72.5% of which occurred at distant sites.

Adoption of AJCC 8th Edition for p16+ Oropharynx Cancers May Result in Decreased Utilization of Adjuvant Therapies Due to Shifts in Pathologic Nodal Staging

The 8th edition of the AJCC (American Joint Committee on Cancer) system no longer includes nodal laterality or size in the pN staging system for p16+ oropharynx cancers. This is because number of involved lymph nodes provides better discriminatory ability for recurrence than laterality, size, or presence of high risk nodal features (i.e. extracapsular extension [ECE]). At our institution, we have routinely offered adjuvant radiotherapy (+/- chemotherapy) for patients with traditional intermediate or high risk features independent of p16 status as per NCCN guidelines. Here, we examine a cohort of p16+ patients staged and treated according to AJCC 7th edition and reclassify them according to the 8th edition to determine rate of nodal downstaging based on the new system. Patients with pathologically node positive p16+ oropharyngeal cancer treated with primary surgery (most commonly TORS with selective neck dissection) followed by adjuvant intensity modulated radiation therapy (+/- chemotherapy) were included for analysis. Demographics, pathology, and treatment details were collected from the electronic medical record. Indications for adjuvant therapy were recorded and patients were re-staged according to the AJCC 8th edition. Rates of nodal downstaging were recorded. A total of 28 patients met inclusion criteria and were treated from 2012 to 2017. 93% were male. 24 (85%) primaries were tonsillar and 4 (15%) base of tongue. An ipsilateral selective neck dissection was performed in 17 (61%) cases. A total of 27 patients had pre-operative imaging (CT or PET) consistent with nodal involvement. The median number of involved lymph nodes was 2 (range 1-8). 13 (46%) had pathologic evidence of ECE, one (4%) microscopic perineural invasion (PNI), and five (18%) had lymphovascular space invasion (LVSI). Five patients (18%) had a microscopically positive margin. AJCC 7th edition N staging was as follows: N1: 10 (36%), N2a: 1 (4%), and N2b: 17 (60%). 15 of 18 (83%) AJCC 7th N2 patients were downstaged to AJCC 8th N1. Seven of these 15 (47%) patients did not have other adverse pathologic features (i.e. pT3, ECE, positive margin, PNI, LVSI). Radiation therapy was delivered using a simultaneous integrated boost technique in all cases. The median dose to the highest risk volume was 60 Gy (range 60-66 Gy). 13 patients (46%) received concurrent chemotherapy. At a median follow up of 25 months (range 3 months to 10 years), there have been no recurrences in this cohort. Nodal downstaging from pN2 to pN1 with the adoption of AJCC 8th edition is common for surgically-treated node positive p16+ oropharynx cancer. Although number of positive nodes has high discriminatory ability for recurrence, it is unknown whether the omission of adjuvant therapy in patients with < 5 positive nodes is safe. Until this is known, the decision to recommend adjuvant therapy should be highly dependent on a thorough understanding of pathologic findings rather than relying purely on the new pathologic N stage.

An Imager's Guide to Perineural Tumor Spread in Head and Neck Cancers: Radiologic Footprints on 18F-FDG PET, with CT and MRI Correlates.

Perineural spread (PNS) refers to tumor growth along large nerves, a macroscopic analog of microscopic perineural invasion. This phenomenon most commonly occurs in the head and neck, but its incidence varies with histologic tumor subtype. PNS results from a complex molecular interplay between tumor cells, nerves, and connective stroma. PNS is clinically underdiagnosed despite its impact on patients' prognosis and management. The role of 18F-FDG PET in assessment of PNS in head and neck cancer remains to be explored, in contrast to MRI as the established gold standard. In patients with PNS, 18F-FDG PET shows both abnormality along the course of the involved nerve and muscular changes secondary to denervation. Assessment of PNS on 18F-FDG PET requires knowledge of relevant neural pathways and can be improved by correlation with anatomic imaging, additional processing of images, and review of clinical context.

Systemic Depletion of Nerve Growth Factor Inhibits Disease Progression in a Genetically Engineered Model of Pancreatic Ductal Adenocarcinoma.

In patients with pancreatic ductal adenocarcinoma (PDAC), increased expression of proinflammatory neurotrophic growth factors (eg, nerve growth factor [NGF]) correlates with a poorer prognosis, perineural invasion, and, with regard to NGF, pain severity. We hypothesized that NGF sequestration would reduce inflammation and disease in the KPC mouse model of PDAC. Following biweekly injections of NGF antibody or control immunoglobulin G, beginning at 4 or 8 weeks of age, inflammation and disease stage were assessed using histological, protein expression, and quantitative polymerase chain reaction analyses. In the 8-week anti-NGF group, indicators of neurogenic inflammation in the dorsal root ganglia (substance P and calcitonin gene-related peptide) and spinal cord (glial fibrillary acidic protein) were significantly reduced. In the 4-week anti-NGF group, TRPA1 mRNA in dorsal root ganglia and spinal phosphorylated ERK protein were elevated, but glial fibrillary acidic protein expression was unaffected. In the 8-week anti-NGF group, there was a 40% reduction in the proportion of mice with microscopic perineural invasion, and no macrometastases were observed. Anti-NGF treatment beginning at 4 weeks may increase inflammation and negatively impact disease. Treatment starting at 8 weeks (after disease onset), however, reduces neural inflammation, neural invasion, and metastasis. These data indicate that NGF impacts PDAC progression and metastasis in a temporally dependent manner.

Treatment Recommendations among Radiation Oncologists in the Treatment of Cutaneous Squamous Cell Carcinoma with Perineural Invasion

Purpose: Post-operative radiotherapy (PORT) for resected cutaneous squamous cell carcinoma (CSCC) with perineural invasion (PNI) is controversial. Therefore, we conducted a survey to review treatment recommendations among Radiation Oncologists (ROs) in the management of CSCC with PNI. Materials & Methods: In March 2011, we contacted all ROs and trainees in the US through email addresses listed in the 2009 ASTRO directory. Our web-based survey presented clinical vignettes involving Mohs micrographically resected CSCC with microscopic PNI (mPNI) or clinical PNI (cPNI). For each vignette, ROs were asked to indicate if PORT was appropriate and to further specify the dose and volume to treat. Results: Three hundred fifty two responses were completed and analyzed. The majority of ROs (72%) had over 10 years of post residency experience. 64% of the sampled ROs had a special interest in treating head and neck cancers, and 64% treated 4 or more cases per year. Approximately 95% recommended PORT for cPNI whereas 59% recommended PORT for mPNI. Post residency experience (10+ yrs vs. = 0.005) and for mPNI of deep subcutaneous non-named nerve involvement (80% vs. 60%, p = 0.001). ROs treating 8 or more cases per year (vs. = 0.01). Conclusions: Our study demonstrates significant variability among ROs in the management of CSCC with mPNI. For cases of cPNI, an overwhelming majority recommended PORT. In cases of mPNI, there was no consensus for recommending PORT, although experienced practitioners had a lower threshold for offering treatment. These results indicate the need for prospective clinical studies to clarify the role of PORT in CSCC patients with mPNI.

Surgical and oncological impact of main pancreatic duct spread in invasive ductal adenocarcinoma: A clinicopathological study of 184 resected cases.

This study examined main pancreatic ductal spread in invasive ductal adenocarcinoma (IDC) of the pancreas. Data from IDC patients who underwent radical surgery from 1990 to 2013 in our hospital were examined retrospectively. Incidence of intraductal spread of pancreatic cancer (IS), distance from the tumor edge, direction of IS and clinicopathological factors associated with the presence of IS were retrospectively examined with data from IDC patients who underwent radical surgery. Among 260 IDC patients who underwent surgery, 184 eligible cases, IS was identified in 42 patients (22.8%) and mean length of IS was 18.7 ± 21.6 mm. Mean distances on the ampullary and distal sides of IS were 11.1 mm and 11.6 mm. IS was significantly more frequent in localized tumors (UICC T1-2 vs. 3-4, p = 0.007), with tumor diameter ≤2 cm (p = 0.034) and in cases with scarce microscopic perineural invasion (p = 0.047). Among patients who underwent pancreaticoduodenectomy and distal pancreatectomy, IS presence (11.6 vs. 21.8%), mean distance to the contralateral side (11.4 vs. 11.6 mm), and IS ≥ 2 cm (3.3 vs. 4.7%) showed no significant differences. Overall survival did not differ significantly between IS-positive and -negative patients in the full analysis set or propensity score-matched patients (42 matched pairs). In setting resectional margins at 2 cm, a small proportion of cases (3.8%) showed positive surgical margins. Localized tumor (UICC: T1-2, or <2 cm in diameter) requires more care with surgical margins, warranting intraoperative frozen sections.

Overexpression of Claudin-1 is Associated with Advanced Clinical Stage and Invasive Pathologic Characteristics of Oral Squamous Cell Carcinoma.

Claudins constitute a group of principal proteins forming the tight junctional complex. The altered expression of selected claudins has been reported in several human cancers. The purpose of this study was to investigate the expression of claudin-1 and claudin-4 in oral squamous cell carcinoma (OSCC) and examine its relationship with patient clinical-pathologic features. Forty-five OSCC cases were enrolled. Patient clinical, pathologic and follow-up data were reviewed and the claudin-1 and claudin-4 expression was analyzed immunohistochemically. Positive claudin-1 and claudin-4 immunoreactivities were noted in 86.7 and 80% of cases, respectively. The majority of cases showed the staining in less than 25% of cancer cells. The increased claudin-1 expression was significantly associated with the high pathologic grade, the presence of microscopic perineural invasion, vascular invasion, nodal metastasis, and advanced clinical stage. No relationship between various clinico-pathologic parameters and differential claudin-4 expression was observed. Claudin-1 may play a role in OSCC progression and could serve as a prognostic marker of advanced disease.

Evaluation of Nerves in Mohs Micrographic Surgery: Histologic Mimickers of Perineural Invasion and Nervous Tissue on Frozen Section

Perineural invasion (PNI) is an important histologic finding and may be a negative prognostic factor for squamous cell carcinoma (SCC). It may be associated with more-aggressive tumor behavior. Mohs surgeons encounter microscopic PNI regularly and must be able to diagnose it accurately to guide care decisions. To describe benign histologic mimickers of PNI and neural structures in SCC commonly encountered on frozen, hematoxylin and eosin-stained sections and to review how to differentiate them from PNI. Review of the literature regarding histologic mimickers of PNI and additional contributions to frozen section PNI and nerve tissue mimickers. We describe benign findings, including arrector pili muscles, eccrine muscles, vessels, granulomatous inflammation, and eddies of SCC, that may each be mistaken for nerves or PNI. We discuss the ways in which they may be distinguished on frozen sections and review other commonly encountered entities that resemble PNI. Perineural inflammation and peritumoral fibrosis are common mimickers of PNI on frozen section, although other mimickers exist on permanent sections. Normal structures may appear "neural" by way of frozen tissue orientation, processing, or inflammation and thus must be differentiated from nerve tissue and PNI during Mohs surgery.

MicroRNA-21 ISH analysis to predict DFS in pancreatic cancer patients undergoing adjuvant gemcitabine after curative surgery.

234 Background: Overexpression of microRNA-21(miR-21) in pancreatic cancer has been reported to be associated with tumor cell proliferation, invasion, and also resistance to gemcitabine (GEM) chemotherapy. The aim of this study was to evaluate whether miR-21 expression, determined by microRNA ISH, was associated with clinical outcomes of pancreatic cancer patients who underwent adjuvant gemcitabine chemotherapy after curative surgery. Methods: Expression levels of miR-21 were semi quantitatively analyzed for staining intensity and distribution of positive tumor cells, by microRNA ISH in formalin-fixed paraffin embedded tissue arrays from 41 pancreatic cancer patients who underwent adjuvant GEM chemotherapy after curative resection at Kanagawa Cancer Center. The staining intensity for the miR-21 was assigned a score from 1 to 3 based on staining with1+: weakly, 2+: moderately, and 3+: strongly positive. The percentage of positive tumor cells was scored as follows, 1+: &lt; 50% positive cells, 2+: 50-80% positive cells, and 3+: ³a 81% positive cells. A composite score was obtained by calculating the sum of these two scores. Results: 27 patients were assigned to low miR-21 expression group (score &lt;4) and 14 patients to high miR-21 group (score 4,5,6). High miR-21 expression group had a significantly shorter DFS (P = 0.039, by log-rank test). The median DFS was 9.8 months (95% CI, 6.9-12.6) in the low miR-21 group, and 7.9 months (95% CI, 6.1-9.8) in the high miR-21 group. The median OS was 19.6 months (95% CI, 6.3-32.8) in the low miR-21 group, and 15.1 months (95% CI, 11.7-18.5) in the high miR-21 group, but was not significant. Multivariate analysis including miR-21 expression, microscopic lymphatic invasion and microscopic perineural invasion, indicated that miR-21 expression (p = 0.024) and microscopic lymphatic invasion (p = 0.035) were the independent predictor for DFS. Conclusions: A high level of miR-21 expression in pancreatic cancer was significantly associated with shorter DFS in patients who received adjuvant GEM after curative resection. miR-21 ISH analysis may serve as a significant predictor for GEM resistance in adjuvant setting.

Perineural Invasion of Head and Neck Skin Cancer: Diagnostic and Therapeutic Implications

Perineural invasion of head and neck skin cancer is a poorly understood and often misdiagnosed pathological entity. Incidental or microscopic perineural invasion is identified by the pathologist and often leads to confusion as to how the patient should be further treated. The less common but more aggressive clinical perineural spread presents with a clinical deficit, which is too commonly misinterpreted by the clinician. This review will try to clarify the terminology that exists in the literature and explore the mechanisms of invasion and spread. It will look at the recent advances in diagnosis and comment on the limitations inherent in current classification schemes. A review of outcomes will be included and current treatment strategies utilized discussed.

Management of Perineural Invasion in Sebaceous Carcinoma of the Eyelid

To report the occurrence and management of perineural invasion in patients with sebaceous carcinoma of the eyelid. An ophthalmology database was searched for all patients treated for sebaceous carcinoma of the eyelid by the principal investigator between May 1999 and May 2010. The clinical records and pathology specimens of the patients with microscopic perineural invasion as an incidental finding in their eyelid surgical specimen were reviewed. Forty-two patients with sebaceous carcinoma of the eyelid were treated by the principal investigator during the study period. Three of them had evidence of microscopic perineural invasion in the surgical specimen. Each patient was treated with surgery with or without radiotherapy. The first patient underwent orbital exenteration and negative sentinel lymph node biopsy, subsequently developed distant metastasis, and died 20 months after exenteration. The second patient underwent resection of the tumor and positive sentinel lymph node biopsy, postoperative irradiation of the eyelid, completion neck dissection and parotidectomy for the positive sentinel lymph node, and irradiation of nodal basins; she was free of disease at last follow up (12 months after tumor resection). The third patient underwent resection of the tumor, developed regional lymph node metastasis 3 months later, underwent lymph node dissection and postoperative nodal irradiation, and was free of disease at last follow up (9 months after tumor resection). Perineural invasion was encountered in 7% of patients with eyelid sebaceous carcinoma. The authors' preference is to treat patients with an incidental finding of microscopic perineural invasion with postoperative adjuvant radiotherapy, ideally within 4 to 6 weeks after surgical resection of the primary eyelid tumor.

Base of skull recurrences after treatment of salivary gland cancer with perineural invasion reduced by postoperative radiotherapy

To determine the effect of postoperative radiation therapy for salivary gland carcinomas in the presence of microscopic perineural invasion. Retrospective review at an academic tertiary center. One hundred and forty patients with pathological evidence of perineural invasion at the time of initial surgery for salivary gland carcinomas were analysed. Sixteen patients (11%) had major (named) nerve involvement. Ninety-four patients (67%) received postoperative radiation therapy to the primary site, and the portal films of 65 of these patients were available for review. The incidence of skull base recurrences among patients treated by surgery with or without postoperative radiation therapy. Ten patients experienced skull base recurrences. T4 disease and the omission of postoperative radiation therapy were identified as significant predictors of skull base recurrence. Postoperative radiation therapy reduced the actuarial probability of skull base recurrence from 15% to 5% (P = 0.03). The crude rates of skull base recurrence were 6% (2/35) and 10% (3/30), respectively, for patients whose skull base were and were not confirmed to be encompassed in the irradiation field. The 5-year overall survival for patients who experienced a skull base recurrence was 19% compared to 91% for those who did not (P < 0.001). The use of postoperative radiation therapy significantly reduced the incidence of skull base recurrence among salivary gland carcinoma patients with perineural invasion.

Histologic mimics of perineural invasion

Perineural invasion (PNI) by primary cutaneous cancers is an important adverse risk factor. Certain benign conditions may mimic microscopic PNI. Mohs surgery is being performed more frequently on smaller primary cutaneous malignancies. While PNI may be present in these cases, it is likely to be microscopic and asymptomatic, affecting as little as one cutaneous nerve branch. Review of the literature base regarding PNI as well as contribution of original findings. Four benign entities that could easily be confused with microscopic PNI are presented. At least four benign mimics of microscopic PNI exist, important in the differential diagnosis of microscopic PNI. Knowledge of these entities should help dermatopathologists to correctly distinguish them from PNI and avoid unnecessary additional treatment.

Postoperative Adjuvant External-Beam Radiation Therapy for Cancers of the Eyelid and Conjunctiva

To outline the indications for and our experience with postoperative adjuvant external-beam radiotherapy (EBRT) in patients with eyelid or conjunctival cancers. Twenty consecutive patients with primary eyelid or conjunctival cancer treated with surgical resection followed by postoperative EBRT between January 2000 and September 2006 were included. The indications for postoperative EBRT, type and dose of EBRT, oculoplastic reconstructive procedures, timing of EBRT in relation to reconstructive procedures, and the ocular side effects of EBRT were recorded. Sixteen women and 4 men ranged in age from 44 to 86 years (median, 64 years). The oculoplastic procedures included local flaps or direct closure of eyelid defect (12), tarsoconjunctival flap (6), full-thickness skin grafts (6), amniotic membrane grafts (2), other conjunctival reconstruction (2), tarsoconjunctival graft (1), and lacrimal stenting (1). The total radiation dose ranged from 26 to 63 Gy (median, 60 Gy). The indications for postoperative EBRT included aggressive histology, recurrent tumor, microscopic perineural invasion, advanced-stage disease, and microscopically positive or "close" margins. EBRT started 5 to 12 weeks (median, 7 weeks) after reconstructive procedures. The follow-up time ranged from 7 to 50 months (mean, 24 months). Thirteen patients experienced dry eye syndrome; 3 keratinization of conjunctiva; and 1 each blepharitis, trichiasis, radiation retinopathy/optic neuropathy, and exposure keratopathy. Postoperative EBRT can be used as adjuvant therapy after surgical resection of eyelid or conjunctival cancers and may obviate more radical surgery such as orbital exenteration in some patients. The ocular side effects from EBRT were relatively minor in most patients.

What is the role of adjuvant radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion?

Perineural invasion (PNI) in cutaneous squamous cell carcinoma (SCC) is infrequent, occurring in 2.5% to 14% of patients, but it is important prognostically, because it carries an increased risk of recurrence and metastasis. Although both excision and Mohs micrographic surgery (MMS) are used to treat SCC with PNI, postoperative radiation therapy (XRT) often is recommended to minimize the risk of recurrence. To date, the effectiveness of adjuvant XRT in this setting has not been determined definitively. The authors evaluated the effectiveness of adjuvant XRT in treating SCC with PNI by performing a thorough literature review. For SCC with PNI, the local control rate after MMS with or without XRT was from 92% to 100% compared with a control rate from 38% to 100% after standard excision with or without XRT. A better prognosis was associated with negative pretreatment magnetic resonance imaging or computed tomography findings than with positive radiographic evidence of PNI. Primary SCC with PNI was associated with better local control than recurrent SCC with PNI. When treatment outcomes were stratified by PNI type, SCC with microscopic PNI and SCC with extensive PNI had local control rates from 78% to 87% and from 50% to 55%, respectively. Adjuvant XRT was associated in selected patients with 100% local control. Few studies addressed the effectiveness of adjuvant XRT in patients who have SCC with PNI. Although XRT has been established as an adjuvant treatment for selected patients, the extent of nerve involvement by tumor, particularly in the setting of other high-risk features, may be helpful in defining its role. In the future, a multicentered, prospective, randomized clinical trial will be needed to assess the true efficacy of adjuvant XRT in the treatment of patients with SCC and PNI.

NeuroD1 Expression in Human Prostate Cancer: Can It Contribute to Neuroendocrine Differentiation Comprehension?

ObjectivesNeuroendocrine differentiation is a common feature of prostate cancer (pCA). NeuroD1 is a neuronal transcription factor able to convert epithelial cells into neurons. The aim of the study is to investigate NeuroD1 expression and compare it with chromogranin-A, synaptophysin, and CD56 staining in human prostate cell lines and surgical specimens. MethodsWe detected NeuroD1 gene expression, by duplex reverse transcriptase-polymerase chain reaction, in primary human prostate fibroblasts, in EPN, LNCaP, DU145, and PC3 cell lines before and after cAMP exposure, in 6 BPH and 11 pCA samples. Thereafter 166 paraffin sections from normal and neoplastic prostates were stained with NeuroD1, chromogranin-A, synaptophysin, and CD56 antibodies. The relationships between chromogranin-A and NeuroD1 and clinicopathologic parameters were evaluated by multivariate logistic regression analysis. ResultsNeuroD1 is inactive in baseline prostate cell lines and BPHs, whereas it is actively expressed in cAMP-treated EPN, PC3, and DU145 cells. In our surgical series, positive chromogranin-A, synaptophysin, CD56, and NeuroD1 staining was detected in 26.5%, 4.3%, 3.1%, and 35.5%, respectively (difference between chromogranin-A and NeuroD1: p<0.05). The multivariate analysis showed a strong association between chromogranin-A and microscopic perineural invasion (OR: 2.49; 95%CI, 0.85–7.32; p=0.097) and a high primary Gleason score (OR: 1.96; 95%CI, 1.14–3.39; p=0.015), whereas NeuroD1 expression strictly correlated to microscopic perineural invasion (OR: 2.97; 95%CI, 1.05–8.41; p=0.04). ConclusionsExpression of NeuroD1 versus chromogranin-A is more frequent in pCA, and correlates to increased indicators of malignancy in moderately to poorly differentiated pCA, and could be involved in the pathophysiology of the neuroendocrine differentiation of pCA.