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Background: Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses., Methods: The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient's prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan-Meier method)., Results: CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2-/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR- (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8-92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5-17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18-3.75, triple-negative and HER2-/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2-8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50-0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65-0.81) for HER2+/HR-, 4.4 months (HR = 1.55, 95% CI: 1.42-1.69) for triple-negative and 7.1 months for HER2-/HR+ patients (p <0.0001)., Conclusions: Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients., Clinical Trial Registration: NCT03275311.

Brain MRI in an 82-year-old man with presumed Bell's palsy revealed a clinically unsuspected right parotid gland mass but no other acute findings. Biopsy revealed poorly differentiated adenocarcinoma. Staging F-FDG PET/CT revealed an FDG-avid parotid mass, abnormal FDG uptake along the course of the facial nerve from mass to skull base, and multiple FDG-avid right level II neck lymph nodes and hepatic metastases. The PET/CT findings and prolonged clinical course suggest that diffuse perineural spread of tumor from a smoldering parotid neoplasm, and not idiopathic Bell's palsy, was responsible for the patient's facial paralysis.

Background: Leptomeningeal carcinomatosis is a rare type of metastatic tumors of the central nervous system. In recent years, with the improvement of neoplasms therapies and longer survival of patients by better systemic control, incidence of leptomeningeal metastases has increased every year. However, there is still lack of effective therapies. The aim of this study is to investigate the efficacy, security and prognosis of intrathecal chemotherapy with methotrexate (MTX) in the treatment of neoplastic meningitis., Methods: A total of 27 patients were enrolled. We investigated clinical features and cerebrospinal fluid (CSF) examination results retrospectively, and analyzed the adverse reactions as well as prognosis after intrathecal chemotherapy., Results: All 27 patients were treated by intrathecal MTX, 70.4% had clinical remission, however, there was no significant difference in CSF pressure and CSF biochemical changes. We observed that 55.6% patients were all appropriate, 25.9% appeared lower limb numbness and mild pain, no serious irreversible adverse reactions occurred. Median overall survival was 4 months., Conclusions: We suggest that intrathecal administration of MTX is associated with improvement of symptoms of leptomeningeal metastasis patients and no severe adverse events observed.

We have previously classified wall invasion patterns of gallbladder carcinoma (GBC) cases into two groups, i.e., the infiltrative growth type (IG type) and destructive growth type (DG type). The DG type was significantly associated with poor differentiation, aggressive infiltration and decreased postoperative survival in terms of its histological differentiation, lymphatic invasion, venous invasion, lymph node status, neural invasion and mode of subserosal infiltration. In the present study, we analyzed 42 surgically-resected subserosal invasive gallbladder adenocarcinomas, invading the perimuscular connective tissue (pT2). The cumulative 5-year survival rate in the series was 48.7%. Lymphatic invasion (p=0.021), venous invasion (p=0.020), mode of subserosal infiltration (p<0.001), histological differentiation (p=0.030) and biliary infiltration (p=0.007) were noted, respectively, at a significantly higher incidence in more aggressive infiltration or poor differentiation in the DG type. The cumulative 5-year survival rate of curative resection cases was lower in patients with the DG type than in those with the IG type (68.9 versus 20.2%, respectively, p=0.006, log-rank test). On Cox's proportional hazard regression modeling, the low degree of venous/perineural invasion and IG type of wall invasion pattern were associated with a significant improvement in overall survival. Our data suggest that the wall invasion pattern is an independent predictor of survival in subserosal invasive GBC. Regarding the clinical application of our concept, on the classification of patients with subserosal invasive GBC based on a combination of the wall invasion pattern and lymph node status, the overall survival rate in patients with the DG type and/or N2 metastasis (n=21) was lower than in patients with the IG type and N0, 1 metastasis (n=21) (p=0.0023, log-rank test). The wall invasion pattern could contribute to decision-making concerning curative resection for subserosal invasive GBC.

Invasion of cranial nerves and peripheral nerve roots, plexus, or nerves by non-Hodgkin lymphoma is denoted as neurolymphomatosis (NL). Four clinical patterns are recognized. Most commonly, NL presents as a painful polyneuropathy or polyradiculopathy, followed by cranial neuropathy, painless polyneuropathy, and peripheral mononeuropathy. Diagnosis of NL is challenging and requires integration of clinical information, imaging findings, and histopathologic examination of involved nerves or nonneural tissue and cerebrospinal fluid analysis. In the rare cases of primary NL, the diagnosis is often delayed. Successful therapy is contingent upon recognition of the disease and its exact neuroanatomic localization without delay. Treatment options include systemic chemotherapy and localized irradiation of bulky disease sites. Concomitant involvement of cerebrospinal fluid and systemic disease sites requires more complex regimens.

Background: In our institution, patients with medullary thyroid carcinoma (MTC) concurrent with nodular goiter (NG) have a nearly 100% survival rate, but the reasons and characteristics are unclear., Methods: Eighty patients with MTC who underwent surgery in our center between 1971 and 2011 were reviewed., Results: A total of 21 MTC/NG and 59 MTC only patients were identified. The stage of the two groups had no significant difference (P = 0.13). The MTC/NG group had lower preoperative serum calcitonin (CT) levels (914.7 ng/L vs. 1162.6 ng/L, P = 0.003), lower postoperative serum CT levels (371.4 ng/L vs. 582.5 ng/L, P < 0.001), lower carcinoembryonic antigen levels (18.3 ng/ml vs. 130.5 ng/ml, P < 0.001), a lower propensity toward lymph node metastasis (40.0% vs. 66.7%, P = 0.07), and a lower proportion of multifocality (19.1% vs. 42.4%, P = 0.06), capsular invasion (9.5% vs. 25.4%, P = 0.21), and vascular invasion (4.8% vs. 10.1%, P = 0.67). The mean tumor diameter of the two groups was similar (20.3 mm vs. 22.1 mm, P = 0.6). Overall 15-year survival in MTC/NG versus MTC only groups was 100% versus 57.0% (P = 0.03)., Conclusions: MTC with NG is an indolent disease and has an excellent prognosis. The only independent predictor of survival was the TNM stage of disease., (Copyright © 2012 Wiley Periodicals, Inc.)

Perineural involvement is a well-recognized clinicopathologic entity found in head and neck (H&N) cancers, including mucosal epithelial carcinomas and salivary gland malignancies. Perineural disease remains a diagnostic, prognostic and therapeutic challenge for the multidisciplinary H&N oncology team. Nerves are important routes of tumor spread in H&N malignancies, yet the biology and prognostic implications of perineural tumor growth are not fully understood. On balance, the available evidence suggests that it is associated with an increased risk of locoregional recurrence but the impact on survival remains uncertain. Perineural involvement has implications for locoregional disease diagnosis and management. MRI is the best imaging modality to detect tumor extent. Advanced radiotherapy technologies such as intensity-modulated radiation therapy and image-guided radiation therapy have the potential for more accurate targeting and treatment of anatomically complex patterns of disease spread. This review is limited to nondermatologic H&N cancers.

Introduction: Small cell lung cancer (SCLC) includes 10-15% of primary lung tumors and it is very aggressive neoplasm. The aim of this study was to evaluate radiological and clinical features of SCLC and its spread., Material and Methods: The retrospective analysis included 31 patients (18 women, 13 men, mean age: 68.2 +/- 8.34 years).The extensive disease (ED) in most patients was present. 25 patients (80,6%) reported habitual cigarette smoking. Localization of primary tumor, metastases, clinical symptoms and main blood abnormalities were assessed., Results: The most common locations of the primary tumor were: the lung hilus--15 (48.4%), the upper lobe of lung--6 (19.3%) and mediastinum--3 (9.7%). In most cases, mediastinal, subcarinal--both (41.9%) and hilus--(32.2%) lymph nodes were involved. Distant metastases were present in 20 patients (64.5%) at the moment of diagnosis. The most common locations of metastases were: liver--12 (60%), lungs--7 (35%), suprarenal glands--6 (30%), bones--3 (15%) and CNS--3 (15%). The most common symptoms were: cough (77.4%), weakness (51.6%), dyspnea (45.2%), chest pain (41.9%) and the weight loss (30%). Superior vena cava syndrome occurred in 4 patients (13%). The symptoms lasted an average 115 days, but the most persistent were: cough (216 days) and dyspnea (150 days). The main blood tests abnormalities were increased activities of: CRP (mean 63.4 mg/L), AspAT (65U), LDH (1852.7 U/l) and D-dimer (1892.5 microg/l)., Conclusions: SCLC was mainly manifested in CT as central mass lung involving hilus or mediastinum. In most cases, distant metastases were present at the moment of diagnosis.

Background: The ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown., Methods: We used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function., Results: Nerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean = 187.1 microm, 95% confidence interval [CI] = 148 to 226 microm vs 14.4 microm, 95% CI = 9.58 to 19.22 microm, difference = 143 microm; P < .001; n = 20). PNMC was induced by secretion of GDNF, via phosphorylation of the RET-Ras-mitogen-activated protein kinase pathway. Nerves from mice deficient in GDNF had reduced ability to attract cancer cells (nerve invasion index: wild type vs gdnf+/-, mean = 0.76, 95% CI = 0.75 to 0.77 vs 0.43, 95% CI = 0.42 to 0.44; P < .001; n = 60-66). Tumor specimens excised from patients with neuroinvasive pancreatic carcinoma had higher expression of the GDNF receptors RET and GRFalpha1 as compared with normal tissue. Finally, systemic therapy with pyrazolopyrimidine-1, a tyrosine kinase inhibitor targeting the RET pathway, suppressed nerve invasion toward the spinal cord and prevented paralysis in mice., Conclusion: These data provide evidence for paracrine regulation of pancreatic cancer invasion by nerves, which may have important implications for potential therapy directed against nerve invasion by cancer.

Objective: Neurological metastases secondary to urological tumors account for 12% overall. The ones derived from germ cells testicular tumors are exceptional in the age of cisplatin., Methods: We report one case of mixed germ cell tumor in a 49-year-old male patient treated with systemic chemotherapy during 18 months before presenting with severe central and peripheral neurological symptoms leading to death due to massive cerebral hemorrhage., Results: We describe three types of presentation of cerebral metastases in patients with testicular cancer. Type I present synchronically with the primary tumor. Type 2 are diagnosed after a period of remission after conventional cytostatic treatment. Type 3 metastases are diagnosed during the course of the disease and its treatment., Conclusions: Except unique metastases classified in groups 1 and 2, which are susceptible of surgery or radiosurgery, in which in response may be expected; the rest of lesions secondary to germ cell tumors have an ominous prognosis and outcomes, with short survivals.

Many cancers can cause disability and pain by invading nerves. In particular, prostate carcinoma has a high propensity for neural invasion (NI) at an early stage. Attempted surgical treatment of tumors with NI often leads to erectile dysfunction and deteriorated quality of life. Therefore, there is a need for novel modalities that will selectively target cancer cells while preserving neural function. Herpes simplex viruses (HSVs) have a natural trophism for peripheral nerves. We hypothesized that oncolytic therapy using HSV engineered to minimize neurotoxicity would be appropriate for this clinical setting. Attenuated HSV (NV1023) injected to sciatic nerves of nude mice had no toxic effect on nerve function (n=30). NV1023 had significant oncolytic effect on prostate carcinoma cells (PC3, DU145, and LNCap) in vitro. An in vivo model of NI was established by implanting prostate carcinoma cells in the sciatic nerves of nude mice. Mice were treated with NV1023 or saline 7 days after establishment of tumors. Significant reduction in tumor size and inhibition of NI was found 6-8 wk after treatment (P<0.005). All animals treated with saline developed complete paralysis <5 wk post-treatment, whereas most NV1023-treated animals had preserved nerve function >12 wk after treatment (P<0.0001). We conclude that oncolytic therapy effectively treats prostate carcinomas with NI in an in vivo murine model while preserving neural function. These findings may hold significant clinical implications for patients with prostate cancer or other neurotrophic tumors.

Purpose: Extra-central nervous system (extra-CNS) metastases are relatively unknown failure patterns in medulloblastoma. The aim of this study was to analyse epidemiological, clinical and aetiopathological aspects of these extra-CNS localisations., Patients and Methods: Extra-CNS metastases were retrospectively identified in patients treated in the department of radiation therapy at Salah-Azaïz institute (ISA) for medulloblastoma. These metastases were diagnosed as extra-CNS for all secondary localisations not related to other tumour aetiology. Aetiopathological aspects are discussed with a literature review., Results: Among 103 patients treated and followed-up in the department of radiation therapy of ISA from 1970 to 1992, 8 developed extra-CNS metastases (7.7%). Age at diagnosis of primitive tumour varied from 3 to 23 years. Sex ratio was 1. Primitive tumour treatment was: complete surgical resection in 4 patients with preoperative cerebrospinal fluid shunting in two, cerebrospinal axis irradiation in 7 patients and a cerebral-limited irradiation in 1. Two patients received chemotherapy for their initial treatment (systemic in one case and intrathecal in the other). The mean free-interval from diagnosis of primitive tumour to extra-CNS metastases was 23 months, varying from 8 to 53 months. These metastases were located in the liver (1 case), cervical lymph nodes (2 cases), bone marrow (1 case) and bone (2 cases). Two patients had multiple metastases: bone and bone marrow (in one), lung, pleura, cervical lymph node and bone localisations (in one). Treatment of these metastases was: chemotherapy in 5 cases, chemotherapy and radiation in one, radiation therapy in one and 2 patients were given only supportive care treatment. All patients died or are in progressive disease in less than one year from the diagnosis of extra-CNS metastases., Conclusion: Extra-CNS metastases are not rare and have a poor prognosis. The most commonly involved sites are bone, cervical lymph nodes and bone marrow. A complete work-up at initial diagnosis is recommended to screen early metastases. Literature review showed that histopathologic grading might help to identify groups at risk.

Background: Neuroblastoma (NB) occurs rarely during adolescence, and information is scarce on its characteristics and clinical course in this age group., Methods: Patients with NB who were included in the Italian Neuroblastoma Registry were considered for the current study. The clinical characteristics and survival of adolescents (age at diagnosis between 10 yrs and 18 yrs) were compared with those of children (ages 1-9 yrs). Infants (age < 1 yr) were excluded because of their well known favorable clinical course., Results: Between 1116 children and 53 adolescents who were evaluated, no differences were documented with regard to the primary tumor site and the prevalence of advanced stage at diagnosis. If only patients with Stage IV NB were considered, then adolescents were less likely to be diagnosed with bone/bone marrow metastases (77%) compared with children (94%; P = 0.038), but adolescents were more likely to have metastases at unusual sites, such as the lung parenchyma or the central nervous system (23% vs. 7%, respectively; P = 0.005). With regard to biologic characteristics, adolescents did not differ significantly from children, although they always had a lower prevalence of unfavorable markers. In particular, MYCN amplification was documented in 21% of children and in 11% of adolescents (P = 0.173). At age 10 years, adolescents had a 20% overall survival rate and a 22% event-free survival rate. Adolescents who had resectable disease had a 73% overall survival rate, which was worse compared with the rate among children with the same disease stage (89%), although the difference did not reach statistical significance (P = 0.159). No differences in survival were observed among patients with Stage IV NB, and adolescents had a probability of survival almost identical to that among children (6% vs. 16%, respectively; P = 0.481). However, when the analysis was restricted to events that occurred after patients developed a recurrence, even if the final outcome was poor for both groups, the difference was statistically significant (P = 0.022) mostly because of the more indolent disease course observed among the adolescents. This effect was even more evident for patients with Stage IV NB. When the 6-year cut-off point was used to separate children from adolescents, a significantly worse overall survival rate (P = 0.036) was documented for adolescents who had resectable disease (81% vs. 93% in children)., Conclusions: NB in adolescents had clinical and biologic characteristics similar to those observed among children. The clinical course of NB probably is correlated significantly with age at diagnosis, but information is scarce on the role of the biologic risk factors in this age group. The authors were able to identify a group of patients with a cut-off age between 6 years and 10 years that had a more indolent course but a worse prognosis., ((c) 2006 American Cancer Society.)

Introduction: Neurological origin and multiple localization of neuroblastoma (NB) in children predisposed to the occurrence of neurological deficits. They usually present as symptoms of spinal cord compression, peripheral nerve palsy or central nervous system metastases. The aim of the study was to analyze retrospectively the frequency and characteristics of neurological disorders in patients with NB, treated in the Department of Paediatrics, Oncology, Haematology and Endocrinology, Medical University of Gdansk, Poland, between 1992 and 2004., Material and Methods: 53 children with NB, aged 1 month to 10 years 10 months were included in the study., Results: Neurological symptoms were present in 16 children (30%), all with advanced NB (stages III and IV). In 12 of them neurological deficits predominated in the medical history, contributing to the neoplasm's diagnosis. Most of the patients (10 children) demonstrated symptoms of the lower limbs paresis and bladder/bowel sphincter dysfunction. Four children suffered from severe back pain. Mentioned neurological disorders preceeded NB diagnosis for median period of 2,5 months. In three patients neurological complications of surgical tumour resection occurred (Horner syndrome in two and foot dorsiflexorparesis in one child). No neurological side effects of chemo- and radiotherapy were observed. Neurological symptoms recovered completely with oncological treatment in eight patients, while in three a considerable neurological improvement was observed. No recovery of neurological deficits was obtained in patients with post-surgical complications and in children suffering from disease progression. Three patients died of NB dissemination, 13 children are alive including two patients undergoing therapy., Conclusions: 1. Most of NB patients recovered completely or partly from neurological disorders while on therapy. Persistent symptoms of neurogenic bladder with accompanying urinary tract infections constitute a considerable clinical problem in some children. 2. NB survivors require intensive interdisciplinary medical care of paediatric oncologist, neurologist, and nephrologist.

Purpose: To determine the analgesic effect of the addition of gabapentin to opioids in the management of neuropathic cancer pain., Patients and Methods: One hundred twenty-one consecutive patients with neuropathic pain due to cancer, partially controlled with systemic opioids, participated in a multicenter, randomized, double-blind, placebo-controlled, parallel-design, 10-day trial from August 1999 to May 2002. Gabapentin was titrated from 600 mg/d to 1,800 mg/d in addition to stable opioid dose. Extra opioid doses were available as needed. Zero to 10 numerical scale was used to rate average daily pain. The average pain score over the whole follow-up period was used as main outcome measure. Secondary outcome measures were: intensity of burning pain, shooting/lancinating pain, dysesthesias (also scored on 0 to 10 numerical scale), number of daily episodes of lancinating pain, presence of allodynia, and daily extra doses of opioid analgesics., Results: Overall, 79 patients received gabapentin and 58 (73%) completed the study; 41 patients received placebo and 31 (76%) completed the study. Analysis of covariance (ANCOVA) on the intent-to-treat population showed a significant difference of average pain intensity between gabapentin (pain score, 4.6) and placebo group (pain score, 5.4; P =.0250). Among secondary outcome measures, dysesthesia score showed a statistically significant difference (P =.0077; ANCOVA on modified intent-to-treat population = 115 patients with at least 3 days of pain assessments). Reasons for withdrawing patients from the trial were adverse events in six patients (7.6%) receiving gabapentin and in three patients receiving placebo (7.3%)., Conclusion: Gabapentin is effective in improving analgesia in patients with neuropathic cancer pain already treated with opioids.

Lateral cervical cysts containing squamous cell carcinoma is a diagnostic and therapeutic challenge for the clinician since they usually represent a cystic metastasis from an occult carcinoma. Various imaging modalities or even blind biopsies will help identify the primary tumour. If the primary tumour is identified, an appropriate treatment decision can be made that incorporates both the primary tumour and the cervical node. If the primary remains unidentified, the neck is treated with a modified or radical neck dissection, depending on the extent of metastatic disease, and radiation therapy is administered to Waldeyer's ring and both necks. We present in this paper, a case with a large cervical cyst where histology showed the presence of a poorly differentiated squamous cell carcinoma in the wall of the cyst. A diagnostic evaluation of the patient was negative. Blind biopsies of the right tonsil revealed occult squamous cell carcinoma. The patient was treated by combined chemo/radiotherapy and she is doing well nine months following excision of the mass. The relevant literature is briefly reviewed.

The natural history of bronchogenic carcinoma shows that 42% of patients are diagnosed with cancer-related neurological complications either at initial presentation or at follow-up that can be separated in 3 different categories: - locoregional involvement of cervicothoracic nerves (recurrent laryngeal nerves, phrenic and vagus nerves, brachial plexus and sympathetic cervical chains), - metastatic disease characterized by intracranial lesions (brain, meningeal, ependymal and pituitary metastases) and spinal (extradural, subarachnoid and medullary metastases) lesions, - paraneoplastic syndromes including limbic encephalitis, Lambert-Eaton syndrome and paraneoplastic cerebellar degeneration. These neurological disorders usually are associated with advanced cancer for which radical surgical management seldom is indicated. All imaging studies performed at the time of initial staging for bronchogenic carcinoma should therefore be carefully reviewed in order to detect signs that could suggest the presence of one or several neurological complications. The goals of this paper are to describe the clinical signs and to illustrate the imaging features of neurological complications related to bronchogenic carcinoma at conventional radiography, CT and MRI.

Background: The purpose of this study was to evaluate the local control, pattern of recurrence, overall survival, and prognostic factors of patients with squamous cell carcinoma (SCC), adenocarcinoma, and undifferentiated carcinoma of the paranasal sinuses (PNS) and nasal cavity (NC) presenting to our center for curative treatment over a 10-year period., Methods: Between 1991 and 2000, 60 patients with SCC (n = 32), adenocarcinoma (n = 25), and undifferentiated carcinoma (n = 3) of the PNS or NC were identified. Forty patients received surgery and postoperative radiotherapy, four surgery alone; 11, radiotherapy alone; three radical radiotherapy after surgical recurrence; one, chemoradiotherapy and surgery; and one, induction chemotherapy followed by radiotherapy., Results: Forty-seven patients (78%) were seen with T3-4 disease; however, most (92%) were node negative on initial assessment. The predominant failure pattern was local disease persistence or recurrence. The estimated 2- and 5-year local control rates were 63% and 49%, respectively. Orbital and neural invasion significantly affected local control. The estimated 2- and 5 year overall survival rates were 57% and 40%, respectively., Conclusions: Local failure remains the dominant cause for poor outcome in this group of patients. Because of the proximity of critical normal structures, the ability to perform adequate surgery and to deliver effective radiotherapy is limited in many cases. The use of postoperative concurrent chemoradiotherapy warrants further investigation., (Copyright 2004 Wiley Periodicals, Inc.)

Nerve pain in cancer is common, mainly manifested by a radiculopathy associated with vertebral metastasis, by a plexopathy caused by lymph-node involvement or, more rarely, by trigeminal involvement in cancer of the head and neck. Less frequent types of nerve pain can occur as late effects of antitumour therapy, including surgery, radiation and chemotherapy. The distinction between a nociceptive and a non-nociceptive nerve pain helps in determining the most appropriate symptomatic management.

Basal cell carcinoma is generally an indolent form of skin cancer. Morpheaform, infiltrative, and sclerosing types are more aggressive tumors. The incidence of perineural invasion in aggressive types of basal cell carcinoma has not been previously described. We studied aggressive basal cell carcinomas for the presence of perineural invasion. Between 1995 and 1998, the histopathologic diagnosis of basal cell carcinoma was made on 5,097 specimens at Dartmouth-Hitchcock Medical Center. Of this total, 507 were classified as sclerosing, infiltrative, or morpheaform. Perineural invasion was found in 15 of the 507 cases. Of these 15 cases, 12 were from the face, and 3 from the back; 13 were recurrent, and 2 were primary lesions. The mean age of patients at diagnosis was 71 years. We found 9.9% of all basal cell carcinomas at our institution to be aggressive types. We found an incidence of perineural invasion of 3% in the aggressive basal cell carcinoma types. This incidence approaches that reported by others for cutaneous squamous cell carcinomas.

Background: The role of chemotherapy dose-intensification in small-cell lung cancer (SCLC) remains unclear. This phase I-II study evaluates feasibility and outcome of combination chemotherapy at moderately elevated doses with concomitant thoracic radiotherapy in limited-disease SCLC., Patients and Methods: Moderately elevated doses of ifosfamide-epirubicin (cycles 1 and 3) and of carboplatin-etoposide (cycles 2 and 4) were given with G-CSF and peripheral blood stem-cell (PBSC) support. Thoracic radiotherapy (40 Gy) was given once daily during the first five days of each cycle., Results: Overall toxicity was acceptable; most common side-effects were myelosuppression and asthenia. All 35 eligible patients responded (23 CR, 12 PR). Median time to progression was 15 months: median overall survival was 24.6 months. Only 6 of 25 relapsing patients (24%) presented with a locoregional recurrence while 12 of 25 (48%) relapsed in the central nervous system (CNS)., Conclusions: This regimen is a feasible dose-intensification with an acceptable toxicity profile. Its efficacy was demonstrated by a 100% response rate, an excellent local tumor control rate and a median survival of 24.6 months. In the absence of PCI, CNS relapse is a major problem if adequate local control is achieved.

18-Fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) has previously been used successfully to image primary and metastatic breast cancer. In this pilot study, 19 breast cancer patients with symptoms/signs referrable to the brachial plexus were evaluated with 18FDG-PET. In 11 cases computerized tomography (CT) scanning was also performed. Of the 19 patients referred for PET study, 14 had abnormal uptake of 18FDG in the region of the symptomatic plexus. Four patients had normal PET studies and one had increased FDG uptake in the chest wall that accounted for her axillary pain. CT scans were performed in 9 of the 14 patients who had positive brachial plexus PET studies; six of these were either normal or showed no clear evidence of recurrent disease, while three CTs demonstrated clear brachial plexus involvement. Of two of the four patients with normal PET studies, one has had complete resolution of symptoms untreated while the other was found to have cervical disc herniation on magnetic resonance imaging (MRI) scan. The remaining two patients almost certainly had radiation-induced plexopathy and had normal CT, MRI and PET study. These data suggest that 18FDG-PET scanning is a useful tool in evaluation of patients with suspected metastatic plexopathy, particularly if other imaging studies are normal. It may also be useful in distinguishing between radiation-induced and metastatic plexopathy.

Background: Neurologic complications of ovarian carcinoma are uncommon and to the authors' knowledge the full spectrum has not been delineated previously., Methods: The authors reviewed the findings of 121 neurologic consultations on 83 ovarian carcinoma patients between 1993 and 1996; this represents 4% of all ovarian carcinoma patients seen at the study institution in this time period., Results: The most common reasons for consultation were altered mental status, pain, weakness, numbness, headache, and seizure. Twenty-seven consultations diagnosed metastatic disease, 14 diagnosed cerebrovascular disease, and 4 diagnosed paraneoplastic syndromes; however, iatrogenic complications (n=38) comprised the majority of diagnoses. Greater than 50% of patients improved neurologically after diagnosis and treatment., Conclusions: Neurologic disease accompanying ovarian carcinoma may be more common and more diverse than recognized previously. Definitive neurologic diagnosis and treatment benefits the majority of patients.

Contribution of one case of renal cells carcinoma, in an adult man, that during evolution developed arachnoid metastasis. The patient was first seen for a brain haemorrhage due to a bleeding metastasis. In later studies, a renal cells carcinoma was found to be the primary site of the brain condition. The evolution showed neurological manifestations in the limbs, and the arachnoid metastasis was detected. The paper includes imaging studies of the referred disease both al brain, renal and spinal level with CT and NMR studies. A revision is made of the different dissemination forms of renal cells tumours, as well as a review of the existing literature with regard to the nervous system metastasis. No case has been found in this review relative to spinal arachnoid dissemination.

The data obtained from various surveys of the epidemiology of the CNS tumors in different countries were analyzed. It was noted, the incidence of primary CNS tumors remains within the limits of 5-12.5 cases per 100,000 people, and depends on number of factors (e.g. sex, age, place of residence, etc.). Metastases double the incidence of all CNS tumors. The estimated incidence of tumors of the nervous system in Russia and particularly Moscow are given in the paper. The analysis of the data cells for the improvement in the organization of the medical care of this group of patients. With this respect the second WHO histological classification of CNS tumors (WHO, 1993) is critically analyzed. Based on the experience at the Burdenko Neurosurgical Institute (over 10,000 brain biopsies), a modified WHO neuropathological classification is suggested. The classification may be useful in research projects, and may facilitate the diagnosis, treatment, rehabilitation, and final assessment of the outcome. Series of documents of this kind help to make the evaluation of the activities of neurosurgical departments more objective, as well as to make the statistics more reliable.

Objectives: The relationship between perineural invasion and prognosis has been demonstrated to be poor in a number of malignancies. This has not been evaluated in the bladder. We performed a study to determine the occurrence of nodal metastases, extranodal metastases, and disease-free survival in patients with perineural invasion (PNI) and/or angiolymphatic invasion (ALI) in transitional cell carcinoma of the bladder (TCCB) from radical cystectomy specimens., Methods: A retrospective review of 27 patients treated with radical cystectomy for TCCB was conducted. Comparisons were performed between three groups: PNI with or without ALI (PNI +/- ALI, 12 patients), ALI alone (8 patients), and a control group (no PNI or ALI) (7 patients)., Results: The mean patient age was 70 years (range 49 to 83). The overall median follow-up period was 11 months (range 1 to 32). PNI +/- ALI was predominantly found in Stage T3b disease (14 of 20 [70%] cases). The overall 1-year disease-free survival was 48%, 67%, and 83% for the PNI +/- ALI, ALI alone, and control groups, respectively. Nodal metastases (for all stages combined) were found in 6 of 12 (50%), 3 of 8 (38%), and 1 of 7 (14%) patients in the PNI +/- ALI, ALI alone, and control groups, respectively. Similarly, extranodal metastatic disease was found in 5 of 12 (42%), 4 of 8 (50%), and 1 of 7 (14%) patients in the PNI +/- ALI, ALI alone, and control groups, respectively. The percentage of deaths for the PNI +/- ALI, ALI only, and control groups were 33%, 50%, and 14%, respectively., Conclusions: In TCCB, perineural invasion with or without angiolymphatic invasion and angiolymphatic invasion alone are associated with a higher incidence of nodal and extranodal metastases and death.

Background: Lymph node status and neural plexus invasion are the most important prognostic factors that may be amenable to surgery for carcinoma of the body and tail of the pancreas. The pattern of lymphatic spread and neural plexus invasion were evaluated by analysis of various clinicopathologic factors., Methods: Twenty patients with carcinoma of the body and tail of the pancreas underwent pancreatectomy with systemic regional lymph node dissection at Kanazawa University Hospital. A precise evaluation of their lymph node involvement and neural plexus invasion was determined., Results: Sixteen of 20 patients (80%) had lymph node involvement. The lymph nodes with a high metastatic rate were those along the splenic artery (50%), the inferior body lymph nodes (35%), the lymph nodes around the common hepatic artery (25%), and the paraaortic lymph nodes (20%). There was no relationship between tumor size, histologic type, and lymph node involvement. Plexus invasion was observed in 14 patients (70%). The most frequent site was the splenic plexus, but between 15% and 20% of the patients had celiac or superior mesenteric plexus invasion. There was no relationship between tumor size, histologic type, and neural plexus invasion., Conclusions: Based on these results, extended lymphadenectomy including the paraaortic lymph nodes, celiac lymph nodes, and superior mesenteric lymph nodes may improve the prognosis for patients with carcinoma of the body and tail of the pancreas. Extrapancreatic neural plexus dissection, especially of the celiac plexus and superior mesenteric plexus, also is necessary.

Background: Neurologic complications of small cell lung cancer (SCLC) are manifold. The incidence and course of the various metastatic and nonmetastatic neurologic disorders were studied prospectively in a cohort of SCLC patients., Methods: The 203 patients underwent neurologic examinations on a regular basis, prior to therapy, during and after treatment, from 1983 through 1994. Routine computer tomography or magnetic resonance imaging of the brain was performed before therapy and after 2 years' survival. Other auxiliary diagnostic tests were performed as required., Results: The majority of the 174 neurologic disorders, diagnosed in 132 patients, were associated with metastases. A total of 79 patients developed brain metastases. The cumulative risk of brain metastases reached 47% for limited and 69% for extensive disease patients at 2 years from diagnosis. Survival following the diagnosis of brain metastases was significantly longer for patients with brain metastases at the initial diagnosis of SCLC than for patients with delayed brain metastases (P < 0.01, long rank test). The most frequent paraneoplastic syndrome with neurologic symptoms was that of inappropriate secretion of antidiuretic hormone (SIADH), which was diagnosed in 11 patients. Antibody-mediated paraneoplastic neurologic syndromes were diagnosed in five patients. Chemotherapy for SCLC caused SIADH to subside in most patients. In contrast, the antibody-mediated syndromes did not respond to SCLC therapy. Adverse effects of treatment included peripheral neuropathy, encephalopathy, radiation plexopathy, and steroid myopathy. However, unlike the other complications, peripheral neuropathy was reversible., Conclusions: This clinical investigation confirmed the frequency of central nervous system metastatic involvement as well as the diversity of the neurologic complications in SCLC. The high frequency of brain metastases justifies a reappraisal of prophylactic cranial irradiation in this patient group.

To determine whether neural invasion or other clinico-pathological factors are prognostic, we performed a retrospective study on 339 rectal carcinomas. The overall 5-year survival was 62%. In the multivariate analysis, age over 60 years, a distance from the anal verge of less than 6 cm, the number of positive lymph nodes, neural invasion and tumour penetration were found to be prognostic. A scoring system identified five prognostic groups of patients. Neural invasion is an independent prognostic factor in our scoring system and it is suggested that this parameter should be taken into consideration for postsurgical treatment.

Neurologic complications of systemic cancer often represent neurologic emergencies. Nonneoplastic neurologic complications are common in cancer patients. Even the treatment of cancer often causes neurotoxicities. Nurses working in critical areas frequently care for these patients. Early diagnosis and treatment improves the patient's outcome in most cases. It is imperative that nurses recognize the signs and symptoms of neurologic complications of systemic cancer.

Thirty patients were examined initially because of neurologic problems and later were diagnosed as having systemic malignant disorders. Acute leukemia was the most common malignancy (36.6%), followed by neuroblastoma (33.3%), non-Hodgkin lymphoma (13.3%), rhabdomyosarcoma (10%), Ewing tumor (3.3%), and Hodgkin lymphoma (3.3%). Four of the 11 acute leukemia patients had nervous system involvement due to meningeal, orbital, or cerebellar infiltration. The complaints of the remaining patients included back pain, weakness, and difficulty in walking, all of which were caused by anemia or bone pain. Neurologic involvement in systemic malignancies, other than acute leukemia, mainly appeared as spinal cord compression (7 with neuroblastoma, 3 non-Hodgkin lymphoma, 1 rhabdomyosarcoma, 1 Ewing tumor), orbital or cavernous sinus infiltration (3 with acute leukemia, 1 rhabdomyosarcoma), and VIIth cranial nerve involvement (2 with rhabdomyosarcoma). One patient had skull infiltration without any neurologic deficit. Cerebellar signs were caused by the remote effects of cancer. It is concluded that acute leukemia is the first and neuroblastoma is the second most common malignancy among childhood systemic malignancies presenting with neurologic involvement; however, neuroblastoma is the most common cause of spinal cord compression.

Carcinoma of the pancreatobiliary system often produces perineural invasion extending to extrabiliary and extrapancreatic sites. A surgical technique has been developed to manage this invasion and has been used since 1974. Serial sections were prepared from 90 resected specimens and examined for perineural involvement of intramural and extramural biliary plexuses as well as the pancreatic nerve plexus. Perineural invasion was seen in 34 of 40 patients with carcinoma of the common bile duct, in ten of 14 with cancer of the gallbladder and in four of 15 with carcinoma of the papilla of Vater. Invasion extended to the extramural biliary or pancreatic nerve plexuses in 24 of 40 patients with carcinoma of the bile duct. Involvement of the intrapancreatic nerves was seen in all 21 patients with carcinoma of the pancreatic head and that of the pancreatic nerve plexus in 17 of 21. Perineural invasion was often found at the most progressive margin of the tumour. The survival rate of patients with perineural invasion was low compared with that of those without such invasion, although survival of patients with perineural invasion tended to be longer after extensive resection. The perineural space should be regarded as an important route for the spread of pancreatic and biliary carcinoma.

4376 basal and squamous cell carcinomas were dealt with over a period of 100 months. 76.6% of these were basal cell carcinomas. Perineural spread was noted in 0.178% of basal cell lesions and in all examples was found in recurrent tumours, which were predominantly in the preauricular and malar areas in this series.

Approximately one cancer patient in five will suffer from injuries to either the central or peripheral nervous system. These complications occur preferentially in the advanced stages of neoplastic disease, and their management is an important aspect of the supportive care of these patients. The most common neurologic complications seen in patients with cancer are related to metastases or to local tumor spread. Antineoplastic treatments, mainly chemotherapy or radiotherapy, account for more than 10% of these complications. A much smaller percentage (probably less than 1%) are paraneoplastic manifestations. In this review, we discuss the most recent developments in the management of neurologic complications specifically related to cancer as well as some less specific problems such as thromboembolic complications and the use of steroids.

We retrospectively evaluated 42 consecutive cancer patients with numb chin syndrome (NCS). Breast cancer comprised 64% of the primary tumors, and lymphoproliferative neoplasms comprised 14%. A standard workup (including imaging of the brain, base of skull, and mandible, and CSF analysis) led to the diagnosis of a metastatic etiology in 89% of the patients. Fifty percent of the patients had mandibular metastases, 14% base-of-skull bone lesions, and 22% leptomeningeal seeding. NCS was a late manifestation of malignancy, associated with disease progression in 67% of the patients or heralding a relapse, which was often confined to the leptomeninges, in 31%. Although various therapeutic strategies led to resolution of NCS, median survival after its diagnosis was 5 months when due to bone metastases and 12 months if associated with leptomeningeal seeding.

To verify the practical utility of immunohistochemical analysis of bone marrow biopsy specimens in patients with neuroblastoma, we compared the results of routine histologic examination of 68 specimens with the results of immunohistochemical detection of tumor cells using an antibody to neuron-specific enolase (NSE). A commercially available polyclonal antibody to this enolase isoform consistently reacted with the neoplastic cells in biopsy specimens with histologic features diagnostic of (24 specimens) or suspicious for (one specimen) metastatic neuroblastoma. Immunohistochemical double-staining techniques documented that the NSE-positive neoplastic cells also reacted with antibodies to chromogranin and synaptophysin. Notably, anti-NSE detected small foci of metastatic neuroblastoma in two of 43 biopsy specimens that showed no evidence of metastatic tumor in the initial histologic sections. Rare NSE-reactive hematopoietic cells were present in approximately a third of the specimens with and those without neuroblastoma and were easily distinguished from metastatic tumor by morphologic examination. We conclude that this antibody to NSE consistently detects neuroblastoma cells in routinely processed bone marrow specimens, including small foci of tumor cells not evident in initial histologic sections.

We treated 109 patients with adult acute lymphoblastic leukemia (ALL) diagnosed by histochemical and immunologic techniques. Patients were excluded only for age greater than 50 years and Burkitt's leukemia. Treatment included a four-drug remission induction phase followed by alternating cycles of noncrossresistant chemotherapy and prolonged oral maintenance therapy. Eighty-eight percent of patients entered complete remission. With a median follow-up of 77 months (range, 48 to 111 months), 42% +/- 6% (SEM) of patients achieving remission are projected to remain disease-free at 5 years, and disease-free survival for all patients entered on study is 35% +/- 5%. Failure to achieve remission within the first 4 weeks of therapy and the presence of the Philadelphia chromosome are associated with a 100% risk of relapse. Remission patients with neither of these adverse features have a 48% +/- 6% probability of remaining in continuous remission for 5 years. Patients with T-cell phenotype have a favorable prognosis with 59% +/- 13% of patients achieving remission remaining disease-free compared with 31% +/- 7% of CALLA-positive patients. Intensive chemotherapy may produce prolonged disease-free survival in a sizable fraction of adults with ALL. Improved therapy is needed, especially for patients with adverse prognostic features.

Neurological involvement with systemic cancer is frequently a cause of major disability. Second to brain metastases, metastasis to the spinal cord and its nerve roots constitutes the most common neurological complication of cancer with an estimated 5 to 10% of patients developing spinal cord involvement that leads to serious impairment of function. With advances in cancer therapy and consequent extension of survival, the overall incidence of neurological complications of cancer is on the rise. Spinal cord dysfunction, while usually nonfatal, leaves the patient with a major neurological disability. The author discusses epidural metastases, highlighting the importance of early recognition and management.

A series of 258 breast cancer patients with known estrogen receptor (ER) status of the primary tumour who subsequently developed metastases were reviewed for site of first metastasis. In 188 cases progesterone receptor (PgR) data were also available. Univariate analysis showed metastatic patterns to differ statistically significantly related to ER status and (less pronounced) PgR status of the primary tumour. Patients with ER-positive tumours had bone metastases three times more often than patients with ER-negative tumours. With respect to PgR-positive and PgR-negative tumours this frequency differed by a factor of two. With regard to visceral metastases ER and PgR status were equally potent prognosticators, patients with receptor negative tumours having a 50% higher frequency of visceral metastasis than patients with receptor positive tumours. Assessment of metastatic patterns in relation to combined receptor status did not substantially enhance the discriminatory value of ER and PgR when assessed separately. Multivariate analysis showed that the observed differences in metastatic patterns were all attributable to differences in the ER status of the primary tumour, and were not influenced by age, menopausal status, axillary lymph node involvement, duration of disease-free interval (DFI), mode of postoperative treatment, or the PgR status of the primary tumour.

Flow cytometric analysis of nuclear DNA content was performed in 26 adenoid cystic carcinomas of the submandibular gland using archived, paraffin-embedded tissues. The DNA content was compared with multiple histologic parameters and clinical course. Ten carcinomas (38%) were aneuploid and 16 (62%) diploid. Aneuploid carcinomas demonstrated a higher frequency of solid cytoarchitecture, lymph node metastases, and advanced clinical stage, as compared with diploid carcinomas. Other histologic features predicting aggressive clinical behavior also correlated with abnormal DNA content and included invasion of nerves larger than 0.25 mm and intravascular extension. Our data suggest that DNA content analysis can be an effective objective parameter in the clinicopathologic assessment of adenoid cystic carcinoma.

Cloacogenic carcinoma is a rare tumor, originating from epithelium of the anal transition zone. We report a 63-yr-old man with pathologically proven cloacogenic carcinoma which caused a rapidly progressive paraparesis and changes in mental status. These were related to extramedullary deposits around the spinal cord and cauda equina and intramedullary deposits in the brain. This pattern of neural involvement with anal canal carcinoma has not been reported previously.