Myxoma of bone in a nonhuman primate

A myxoma of the mandibles in an adult female Macaca mulatta is described. The left mandible was markedly enlarged by the tumor, which extended from the symphysis to the temporomandibular joint. The tumor had extended a short distance across the symphysis into the right mandible. It was composed of a glistening mucinous material. Radiographs of the tumor showed a large expansile radiolucent lesion of the left mandible without soft tissue involvement. Light microscopy demonstrated capillaries, stellate shaped cells with processes up to 15 mu long, very few other cell types, and an amorphous ground substance. Electron microscopic examination revealed similarity to the myxoma of bone of man. The oxytalan fibers discovered in this myxoma have not been found in myxomas before and suggest the tumor is odontogenic in origin. The incidence of spontaneous neoplasia in general and that of spontaneous oral tumors in particular in nonhuman primates are reviewed.     

Neuroblastic and Schwannian stromal cells of neuroblastoma are derived from a tumoral progenitor cell

The coexistence of neuroblastic and Schwannian stromal (SS) cells in differentiating neuroblastoma (NB), and derivation of Schwannian-like cells from neuroblastic clones in vitro, were accepted previously as evidence of a common pluripotent tumor stem line. This paradigm was challenged when SS cells were suggested to be reactive in nature. The advent of microdissection techniques, PCR-based allelic analysis, and in situ fluorescent cytometry made possible the analysis of pure cell populations in fresh surgical specimens, allowing unequivocal determination of clonal origins of various cell subtypes. To overcome the complexity and heterogeneity of three-dimensional tissue structure, we used: (a) Laser-Capture Microdissection to obtain histologically homogeneous cell subtype populations for allelotype analysis at chromosomes 1p36, 11q23, 14q32, and 17q and study of MYCN copy number; (b) multiparametric analysis by Laser-Scanning Cytometry of morphology, DNA content, and immunophenotype of intact cells from touch imprints; and (c) bicolor fluorescence in situ hybridization on touch imprints from manually microdissected neuroblast and stroma-rich areas. Histologically distinct SS and neuroblastic cells isolated by Laser-Capture Microdissection had the same genetic composition in 27 of 28 NB analyzed by allelic imbalance and gene copy number. In all 20 cases studied by Laser-Scanning Cytometry, SS cells identified by morphology and S-100 immunostaining had identical DNA content and GD2-staining pattern as their neuroblastic counterparts. In 7 cases, fluorescence in situ hybridization demonstrated the same chromosomal makeup for SS and neuroblastic cells. These results provide unequivocal evidence that neuroblastic and SS cells in NB are derived from genetically identical neoplastic cells and support the classical paradigm that NB arises from tumoral cells capable of development along multiple lineages.     

Histopathologic features of composite ganglioneuroblastoma. Immunohistochemical distinction of the stromal component is related to prognosis

Histopathologic features of 18 cases of composite ganglioneuroblastoma (CGNB) were studied with immunohistochemical staining techniques using antibodies against S-100 protein (S-100), ferritin (FER), and leukocytic common antigen (LCA). Cases of CGNB were divided on the basis of the morphologic features of neuroblastic elements into three prognostic subgroups: "Type A Intermixed," having individual microscopic nests of neuroblasts (N = 4, 100% survival); "Type B Intermixed," having microscopic aggregates of multiple neuroblastic nests (N = 6, 67% survival); and "Nodular," having grossly visible nodule(s) of neuroblastic proliferation (N = 8, 0% survival). Survival rates are significantly different for the prognostic subgroups (P less than 0.025). Each prognostic subgroup demonstrated an immunohistochemically distinct pattern of stromal cell composition in the neuroblastic elements: Type A Intermixed had numerous S-100 cells and no FER cells, Type B Intermixed contained many S-100 cells and a moderate number of FER cells, and Nodular had few S-100 cells with many FER cells. The S-100 and FER scores, determined by counting the positive cells through a line sampling method, differed significantly between these prognostic subgroups. Lymphocytic aggregations in tumor tissue evaluated by volumetric assessment with LCA staining, on the other hand, showed no contribution in predicting the outcome of the patients. There was also an inverse relationship between S-100 and FER score, suggesting a relationship between the relative predominance of these stromal cell types, tumor histopathologic features, and the biologic behavior of CGNB.     

Dickkopf-3 expression is a marker for neuroblastic tumor maturation and is down-regulated by MYCN

Neuroblastoma and ganglioneuroma are neuroblastic tumors originating from the developing sympathetic peripheral nervous system. Ganglioneuromas are usually benign, while neuroblastomas have a variable prognosis and include very aggressive tumors. Examples exist of neuroblastomas regressing to ganglioneuromas and ganglioneuromas progressing to neuroblastomas. Little is known of the molecular differences between the tumor types. Here we report that Dickkopf-3 (DKK3), a putative extra cellular inhibitor of the Wnt/beta-catenin pathway, showed a strongly differential expression between neuroblastoma and ganglioneuroma. Microarray analyses of 109 neuroblastic tumors revealed that DKK3 is strongly expressed in ganglioneuroma but only weakly in neuroblastoma. Low DKK3 expression in neuroblastoma correlated with a poor prognosis. The expression of DKK3 in the tumor series and in neuroblastoma cell lines was inversely correlated with the expression of the MYCN oncogene. Analysis of 2 neuroblastoma cell lines with inducible activity of MYCN showed that DKK3 is down-regulated by MYCN. We subsequently generated cell lines with inducible expression of DKK3, which revealed an inhibitory effect of DKK3 on proliferation. High DKK3 expression in the benign ganglioneuromas and down-regulation of DKK3 by MYCN in neuroblastoma might contribute to the strongly different clinical behavior of both neuroblastic tumor types.     

Tubedown expression correlates with the differentiation status and aggressiveness of neuroblastic tumors.

PURPOSE: The discovery and validation of new prognostic factors and further refinement of risk group stratification are needed to improve clinical interpretation of neuroblastoma. Our laboratory isolated and characterized a developmentally regulated gene named TUBEDOWN against which we have raised a monoclonal antibody (OE5). Tubedown becomes down-regulated postnatally yet remains strongly expressed in some neuroblastomas. The purpose of this study is to define the utility of Tubedown expression as a new measure of the differentiation status and aggressiveness of neuroblastic tumors. EXPERIMENTAL DESIGN: Tubedown protein expression was quantitatively assessed in neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) and normal adrenal tissues using Western blot and OE5 immunohistochemistry. Regulation of Tubedown expression during retinoic acid-induced neuronal differentiation in neuroblastoma cell lines was assessed by Western blotting. RESULTS: High levels of Tubedown expression are observed in tumors with significant neuroblastic component, unfavorable histopathology, advanced stage, high-risk group, and poor outcome. In contrast, more differentiated subsets of neuroblastic tumors, ganglioneuroblastomas with favorable histopathology and ganglioneuromas, express low levels of Tubedown. In vitro, marked retinoic acid-induced neuronal differentiation responses of neuroblastoma cells are associated with a significant decrease in Tubedown expression, whereas limited neuronal differentiation responses to retinoic acid were associated with little or no decrease in Tubedown expression. CONCLUSIONS: Our results indicate that the levels of Tubedown expression are linked to the differentiation status and aggressiveness of neuroblastic tumors and represent an independent prognostic factor for neuroblastoma. Tubedown expression may be useful to more accurately define different neuroblastic tumor subsets and ultimately provide more adequate assessment and treatment for neuroblastoma patients.     

Pathology of peripheral neuroblastic tumors: Significance of prominent nucleoli in undifferentiated/poorly differentiated neuroblastoma

The presence of large cells having simultaneously increased cytoplasmic and nuclear volume accompanied by prominent nucleoli; i.e., differentiating neuroblasts and ganglion cells, is well documented in peripheral neuroblastic tumors (pNTs), and considered as one of the signs of tumor maturation and an indication of a better prognosis of the patients. On the other hand, in 2004 it was reported that large-cell neuroblastoma composed of neuroblastic cells with only nuclear enlargement without recognizable cytoplasmic maturation behaved poorly clinically. Here we are proposing a new pNT subtype in the neuroblastoma category, in addition to the undifferentiated, poorly differentiated and differentiating subtypes: that is large nucleolar neuroblastoma (LNN) characterized by large prominent nucleoli and no or very little amount of discernible cytoplasm. LNN, whose neuroblastic cells are often large in size due to nuclear enlargement, includes those tumors previously categorized into the large-cell neuroblastoma group. LNN tumors, regardless of the size of nuclei, seem to behave aggressively with a very poor prognosis of the patients. It is speculated that nucleolar enlargement without cytoplasmic maturation in LNN tumor cells can be a sign of MYCN amplification.     

Imaging of parotid gland primitive neuroectodermal tumor

A seven-years-old boy presented with recurrent episodes of right parotid gland swelling that was presumptively being treated as sialoadenitis. Interrogation with ultrasonography, computerized tomography and magnetic resonance imaging revealed a heterogeneous mass occupying the right parapharyngeal space, imperceptibly merging with adjoining parotid gland, scalloping the vertical ramus of the mandible and involving the base skull with widening of the foramen ovale. The findings at surgery and histopathology provided a final diagnosis of parotid gland primitive neuroectodermal tumor. This report emphasizes on the imaging findings of this rare tumor occurring in such an unusual location.     

The low‐affinity neurotrophin receptor,p75, is upregulated in ganglioneuroblastoma/ganglioneuroma and reduces tumorigenicity of neuroblastoma cells in vivo

Neuroblastoma, the most common extracranial tumor of childhood, is derived from neural crest progenitor cells that fail to differentiate along their predefined route to sympathetic neurons or sympatho‐adrenergic adrenal cells. Although expression of the high‐affinity neurotrophin receptors, TrkA and TrkB, is of major importance in neuroblastoma, the significance of the expression of the low‐affinity neurotrophin receptor, p75, is unclear. Here, we analyzed immunohistochemically expression of p75 on a tissue microarray of 93 primary neuroblastic tumors and assessed the functional consequences of p75 expression in neuroblastoma cell lines. We found the p75 receptor protein to be expressed in neuroblastic cells of ganglioneuromas/ganglioneuroblastomas as well as differentiating neuroblastomas, but not in poorly differentiated neuroblastomas. In an unrelated cohort of 110 neuroblastic tumors, p75 mRNA expression levels correlated with differentiation, and patients with tumors that expressed p75 at high levels had an increased event‐free and overall survival. In addition, we did not detect p75 expression in 8 established neuroblastoma cell lines examined with FACS analysis. These cell lines exhibited an undifferentiated morphology, and were all derived from aggressive, high‐stage neuroblastomas. Ectopic p75 expression in the SH‐SY5Y neuroblastoma cell line significantly reduced proliferation, increased the fraction of apoptotic cells in vitro and resulted in a loss of tumorigenicity in nude mice. Taken together, our data suggest that expression of the p75 low‐affinity neurotrophin receptor is correlated with a reduced level of tumorigenicity, and that induction of p75 expression may be an option to revert features of an aggressive tumor phenotype. © 2008 Wiley‐Liss, Inc.     

Spindle-cell ameloblastic carcinoma: A case report with immunohistochemical,ultrastructural, and comparative genomic hybridization analyses

Spindle-cell ameloblastic carcinoma is a classification proposed for a group of rare odontogenic carcinomas with sarcomatoid components and is distinguished from odontogenic carcinosarcoma. We report a case of spindle-cell ameloblastic carcinoma of the right mandible that occurred in a 67-year-old Japanese man. Growth of the tumor was destructive, there was extensive lung metastasis, and the outcome was unfavorable. Ultrastructural and immunohistochemical examination showed the spindle-cell component of the tumor to be epithelial in character. A gain of 5q with amplification of 5q13 was detected in the tumor by comparative genomic hybridization.     

GRP78 expression correlates with histologic differentiation and favorable prognosis in neuroblastic tumors

Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum protein, is essential for the differentiation of neuroblastoma cells and is selectively induced when the cells are undergoing apoptosis. These findings suggest that GRP78 may affect the tumor behavior of neuroblastoma. Our study evaluates the association of clinicopathologic factors and patient survival with the expression of GRP78 in patients with neuroblastoma. GRP78 expression in 68 neuroblastic tumors was investigated semiquantitatively by immunohistochemistry. GRP78 mRNA and protein levels in 7 tumor tissues were also quantified by real-time PCR and Western blot respectively and correlated well with the immunohistochemical results. Forty (58.8%) of the 68 neuroblastic tumors showed positive GRP78 expression. The percentage of positive GRP78 immunostaining increased as the tumor histology became differentiated (p = 0.001). Furthermore, positive GRP78 expression strongly correlated with early clinical stages (P = 0.002) but inversely correlated with MYCN amplification (p = 0.001). Kaplan-Meier analysis showed that patients with positive GRP78 expression did have better survival than those with negative expression (5-year survival rate, 72.9% and 23.4% respectively, p < 0.001). Multivariate analysis further showed that GRP78 expression was an independent prognostic factor. Moreover, GRP78 expression predicted better survival in patients with either undifferentiated or differentiated histologies. GRP78 expression still had significant prognostic value when the analysis was restricted to tumors of advanced stages or without MYCN amplification. Thus, GRP78 can serve as a novel independent favorable prognostic factor for patients with neuroblastoma.     

Expression of prenylated Rab acceptor 1 domain family, member 2 (PRAF2) in neuroblastoma: correlation with clinical features, cellular localization, and cerulenin-mediated apoptosis regulation.

PURPOSE: Prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is a novel 19-kDa protein that has recently been implicated in human cancer. In the present study, we analyzed for the first time PRAF2 mRNA expression in a large set of human tumors. The high expression in neuroblastic tumors prompted us to analyze PRAF2 expression correlations with genetic and clinical features of these tumors. In addition, we determined the localization of PRAF2 protein in neuroblastoma cells and studied its regulation in apoptosis. EXPERIMENTAL DESIGN: Affymetrix microarray analysis was done with a set of 41 different tumor types (1,426 samples) in the public domain, a set of three different neuroblastic tumor types (110 samples), and a panel of 25 neuroblastoma cell lines. The subcellular localization of endogenous PRAF2 in neuroblastoma cells was identified by immunofluorescence microscopy and apoptosis detected by Annexin V staining and poly(ADP-ribose) polymerase cleavage. RESULTS: PRAF2 mRNA was detected in 970 of 1,426 samples in the public data set. All 110 neuroblastic tumors expressed PRAF2 at higher levels than any other tumor examined. Importantly, PRAF2 expression levels significantly correlated with the following clinical features: patient age at diagnosis (P = 6.19 x 10(-5)), survival (P = 1.32 x 10(-3)), International Neuroblastoma Staging System stage (P = 2.86 x 10(-4)), and MYCN amplification (P = 3.74 x 10(-3)). PRAF2 localized in bright cytoplasmic punctae and protein levels increased in neuroblastoma cells that underwent cerulenin-induced apoptosis. CONCLUSIONS: Elevated PRAF2 expression levels correlated with unfavorable genetic and clinical features, suggesting PRAF2 as a candidate prognostic marker of neuroblastoma.     

TrkA expression in peripheral neuroblastic tumors: prognostic significance and biological relevance

BACKGROUND: This study was conducted to investigate the prognostic significance and biologic relevance of trkA expression levels in peripheral neuroblastic tumors (pNTs) (i.e., neuroblastoma, ganglioneuroblastoma, and ganglioneuroma). METHODS: Levels of trkA expression from a total of 265 pNTs were determined by quantitative polymerase chain reaction analysis with Genescan software. The results were analyzed according to histopathology (favorable histology [FH] vs. unfavorable histology [UH] according to the International Neuroblastoma Pathology Classification) and MYCN tumor status (amplified vs. nonamplified) along with clinical stage and outcomes of the patients. RESULTS: The levels of trkA expression differed significantly between the group of patients who were alive and well (n = 170 patients) and the group that had progressed or died (n = 95 patients) and between the group that was alive (n = 188 patients) and the group that died (n = 77 patients). However, the trkA expression levels were not independent predictors of clinical outcome when the proportional hazards model contained the known prognostic variables of clinical stage, histopathology, and MYCN status (all tests were done in 196 patients). In the neuroblastoma category (n = 173 tumors), tumors in the FH/nonamplified MYCN subset (n = 112 tumors) expressed higher levels of trkA and showed an age-dependent neuroblastic differentiation: They were classified into either a poorly differentiated subtype (n = 91 tumors; all patients age < 1.5 years at diagnosis) or a differentiating subtype (n = 21 tumors; 57% of patients ages 1.5-5.0 years). Tumors in the UH/amplified MYCN subset (n = 30 tumors) expressed significantly lower levels of trkA and showed very limited neuroblastic differentiation. Tumors in the FH/amplified MYCN subset were very rare (n = 3 tumors) and expressed higher levels of trkA. Tumors in the UH/nonamplified MYCN subset (n = 28 tumors) had trkA levels in a wide range and showed limited neuroblastic differentiation. CONCLUSIONS: For patients with pNTs, levels of trkA expression did not add significant information to prognostic grouping, as defined by the combination of clinical stage, histopathology, and MYCN status. There was a biologically relevant correlation between molecular properties (trkA expression and MYCN status) and histopathologic features of the tumors in the neuroblastoma category.     

Genome‐wide DNA methylation analysis of neuroblastic tumors reveals clinically relevant epigenetic events and large‐scale epigenomic alterations localized to telomeric regions

The downregulation of specific genes through DNA hypermethylation is a major hallmark of cancer, although the extent and genomic distribution of hypermethylation occurring within cancer genomes is poorly understood. We report on the first genome‐wide analysis of DNA methylation alterations in different neuroblastic tumor subtypes and cell lines, revealing higher order organization and clinically relevant alterations of the epigenome. The methylation status of 33,485 discrete loci representing all annotated CpG islands and RefSeq gene promoters was assessed in primary neuroblastic tumors and cell lines. A comparison of genes that were hypermethylated exclusively in the clinically favorable ganglioneuroma/ganglioneuroblastoma tumors revealed that nine genes were associated with poor clinical outcome when overexpressed in the unfavorable neuroblastoma (NB) tumors. Moreover, an integrated DNA methylation and copy number analysis identified 80 genes that were recurrently concomitantly deleted and hypermethylated in NB, with 37 reactivated by 5‐aza‐deoxycytidine. Lower expression of four of these genes was correlated with poor clinical outcome, further implicating their inactivation in aggressive disease pathogenesis. Analysis of genome‐wide hypermethylation patterns revealed 70 recurrent large‐scale blocks of contiguously hypermethylated promoters/CpG islands, up to 590 kb in length, with a distribution bias toward telomeric regions. Genome‐wide hypermethylation events in neuroblastic tumors are extensive and frequently occur in large‐scale blocks with a significant bias toward telomeric regions, indicating that some methylation alterations have occurred in a coordinated manner. Our results indicate that methylation contributes toward the clinicopathological features of neuroblastic tumors, revealing numerous genes associated with poor patient survival in NB.     

Mental neuropathy (numb chin syndrome). A harbinger of tumor progression or relapse.

The authors report four patients whose initial symptom of tumor recurrence or progression was unilateral numbness of the chin. Two patients had Hodgkin lymphoma, one had malignant melanoma, and one had prostate cancer. Physical examination was notable only for unilateral anesthesia of the chin and lower lip. Diagnostic evaluation, including computed tomography (CT) scan and magnetic resonance imaging (MRI) of the brain, plain radiographs of the mandible, and cerebrospinal fluid analysis for protein, glucose, and cytology were normal. Bone scans revealed osseous lesions in the axial skeleton of all patients, whereas only two patients had abnormal uptake in the mandible. The authors conclude that in the setting of a negative evaluation for central nervous system (CNS) or local mandibular disease, mental neuropathy is associated with recurrent or progressive skeletal disease. In addition, to document relapsed or progressive cancer, the skeletal system may have to be examined at sites distant from the mandible.     

Ultrastructure of primitive neuroectodermal neoplasms of the central nervous system.

The ultrastructure of one spinal and five cerebral neoplasms diagnosed by light microscopy as primitive neuroectodermal tumors supports a cell population consisting largely of poorly differentiated neuroepithelial cells. The most unique ultrastructure feature was the presence of annulate lamellae in four of the six cases. Glial cells in the neoplasm were not unequivocally of neoplastic origin and were possible reactive. There was no evidence of neuroblastic or neuronal elements, although there was frequently focal early neuroblastic differentiation by light microscopy. Although we have seen neoplasms which are clearly neuroblastic, these particular tumors are not purely neuroblastic and should not be classified as neuroblastomas.     

Melanotic neuroectodermal tumor of infancy. A review of seven cases

The melanotic neuroectodermal tumor of infancy (MNTI) is a rare, usually benign, pigmented neuroectodermal tumor which most often involves the maxilla. The authors reviewed seven cases of MNTI, with patient ages of our patients ranged from nine weeks to 18 months; six of the seven were less than six months old at initial diagnosis. Four patients were males, and all were white. One tumor each was located in the femur, the temporal bone, and the epididymis; the remaining lesions occurred in the maxilla. Three of the four maxillary tumors recurred locally; the epididymal and femoral tumors metastasized. Two of these cases had unique clinical or pathologic features. The case of the femoral tumor is remarkable in that it is the first reported one of MNTI presenting in a long bone. This tumor was aggressively malignant; within two months after its discovery, a large mass of similar tumor was formed in the pelvis, and the tumor resulted in the patient's death. To the authors' knowledge, the case of the temporal bone tumor is the first one of MNTI in which neuronal differentiation of the neuroblastic cells is convincingly demonstrated. This finding provides additional evidence in support of the neuroectodermal theory of origin of these neoplasms.     

Maturation of cerebellar neuroblastoma into ganglioneuroma with melanosis. A histologic, immunocytochemical, and ultrastructural study

A ganglioneuroma with areas of melanosis was resected from the cerebellum of a 6.5-year-old girl. At 2.5 years of age, she was diagnosed to have cerebellar neuroblastoma, which was incompletely resected and then radiated. Histologic, ultrastructural, and immunocytochemical studies undertaken on tissue from both stages of the tumor demonstrated a neuroblastic origin and differentiation into a predominantly neuronal tumor with limited astroglial participation. In addition, widespread deposition of basal lamina material, perineuronal distribution of S-100 protein-bearing cells and melanosis were found. The various features and unusual biology of the tumor are discussed in the light of a review of the literature.     

Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group.

BACKGROUND: The International Neuroblastoma Pathology Classification (International Classification), which was established in 1999, is significant prognostically and is relevant biologically for the evaluation and analysis of patients with neuroblastic tumors (NTs). MYCN amplification is a known molecular marker for aggressive progression of NTs. These have been used together as important prognostic factors to define risk groups for patient stratification and protocol assignment. METHODS: A total of 628 NTs (535 neuroblastomas [NBs]); 21 ganglioneuroblastoma, intermixed [GNBi]; 9 ganglioneuromas [GN]; and 63 ganglioneuroblastoma, nodular [GNBn]) from the Children's Cancer Group studies were evaluated histologically (favorable histology [FH] tumors vs. unfavorable histology [UH] tumors) according to the International Classification and were tested molecularly for MYCN status (amplified vs. nonamplified). Four tumor subsets (FH-nonamplified, FH-amplified, UH-nonamplified, and UH-amplified) were defined by histopathology and MYCN status, and their prognostic effects were analyzed. Detailed analysis between morphologic indicators (grade of neuroblastic differentiation and mitosis-karyorrhexis index [MKI]) and MYCN status was done by using tumors in the NB category. RESULTS: There were 339 FH-nonamplified tumors (5-year event free survival [EFS], 92.1%); 8 FH-amplified tumors (EFS, 37.5%); 172 UH-nonamplified tumors (EFS, 40.9%); and 109 UH-amplified tumors (EFS, 15.0%). The prognostic effects on patients with tumors in the four subsets were independent from the factors of patient age and disease stage (P < 0.0001). MYCN amplification was seen almost exclusively in tumors of the NB category, and no patients with tumors in either the GNBi category or in the GN category and only two patients with tumors in the GNBn category had amplified MYCN. Among the patients with tumors in the NB category, patients with FH-nonamplified tumors (309 patients) had an excellent prognosis, and patients with UH-amplified tumors (107 patients) had the poorest clinical outcome in any age group. The prognosis for children with UH-nonamplified tumors (111 patients) was poor when they were diagnosed at age > 1.5 years. It was also noted that patients with UH-amplified tumors (median age, 2.14 years) were diagnosed at a significantly younger age compared with the patients with UH-nonamplified tumors (median age, 3.55 years). Histologically, MYCN-amplified tumors lacked neuroblastic differentiation regardless of the age of patients. MYCN amplification also was linked generally to increased mitotic and karyorrhectic activities. However, MKI classes in patients with MYCN-amplified tumors varied significantly, depending on the age at diagnosis, and younger patients had higher MKI classes. CONCLUSIONS: The combination of histopathologic evaluation and MYCN status distinguishes four clinical and biologic tumor subsets in patients with NTs. MYCN amplification seems to be the powerful driving force for preventing cellular differentiation regardless of patient age and for increasing mitotic and karyorrhectic activities in an age dependent manner.     

Unusual manifestations of multiple cranial nerve palsies and mandibular metastasis in a patient with squamous cell carcinoma of the lip

A 70-year-old man who had squamous cell carcinoma of the lip later presented with right mental neuropathy, ipsilateral progressive involvement of all three divisions of the 5th, the 7th and 8th cranial nerves, and complete ophthalmoplegia. Biopsy proven metastasis to the mandible was demonstrated. Although repeated studies of CT scan of the head and cerebral angiography were negative, CSF examination revealed positive cytology, elevated protein and low sugar content. Although vascular dissemination from the primary lip lesion to the mandible and brain stem cannot be ruled out, extension through perineurial space via the 5th cranial nerve have been speculated. This case demonstrates two unusual features of squamous cell carcinoma of the lip, namely metastasis to the mandible and meningeal spread with multiple cranial neuropathies.