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We report the case of a voluminous melanotic neuroectodermic tumor, also termed melanotic progonoma, which developed in a 5 month old infant, recalling the main aspects of such uncommon non-odontogenic tumors with characteristic histological features. The large size of the tumor can hinder feeding in infants. Surgical cure is generally easy and outcome quite satisfactory without recurrence.
Ewing's sarcoma (ES) initially was believed to be of perivascular endothelial origin. The Ewing's sarcoma family of tumors (EFT) includes ES of bone (ESB), extraosseous ES (EES), peripheral primitive neuroectodermal tumor of bone (pPNET), and malignant small-cell tumor of the thoracopulmonary region, or Askin's tumor, all of which are now known to be neoplasms of neuroectodermal origin. The degree of neuronal differentiation has been used for histopathologic subclassification of the EFT as classical ES (ESB or EES), which is characterized by minimal evidence of neural differentiation, and pPNET, which displays evidence of neural differentiation by standard microscopy, electron microscopy, or immunohistochemistry. Because the behavior, prognosis, and treatment appear to be similar for all subsets of EFT, this histopathologic subclassification may not be clinically significant, though some debate remains whether neural differentiation predicts for inferior outcome.
We report a pigmented intraosseous odontogenic carcinoma of the maxilla occurring in a 6-year-old Japanese boy. Grossly, the tumor showed solid, gray-yellow, and markedly pigmented appearance. Histology showed neoplastic growths of atypical epithelial cells that occasionally contained melanin pigments. Melanocytes with dendritic processes were often found in the tumor cell clusters, and solitary or aggregated melanophages were scattered within the dense fibrovascular stroma. The tumor cells were diffusely positive for cytokeratins and epithelial membrane antigen, and focally positive for vimentin, neuron specific enolase, neurofilament protein, carcinoembryonic antigen, and amelogenin. Ultrastructural studies showed well-developed intercellular junctions, mainly desmosomes, and glycogen particles. In addition, some tumor cells contained melanosomes and/or a few neurosecretory granules. We consider that the present tumor suggests a close association of ectoderm, mesenchyma, and neuroectoderm in embryogenesis of the tooth, and can raise a diagnostic confusion with melanotic neuroectodermal tumor.
The pattern of CD-34 antigen (human progenitor cell antigen) immunoreactivity was studied within normal nerve, and a variety of nerve sheath and neuroectodermal tumors. Besides normal nerves, 111 soft tissue tumors were studied, including 17 neurofibromas, 10 neurilemomas, 12 malignant peripheral nerve sheath tumors, 1 melanocytic schwannoma, 21 fibroblastic lesions, 31 fibrohistiocytic lesions, seven neuroectodermal lesions, and 10 miscellaneous tumors. CD-34-positive dendritic cells were consistently identified within the endoneurium of normal nerve, all neurofibromas, dermatofibrosarcomas, and Antoni B (but not Antoni A) areas of neurilemomas. CD-34 was not expressed in the majority (eight of 10 cases) of malignant peripheral nerve sheath tumors. CD-34 was also lacking in all fibroblastic lesions (nodular fasciitis, fibromatosis, keloid, fibrosarcoma) and in neuroectodermal tumors that are not generally considered to show true nerve sheath differentiation (neurotropic melanoma, clear cell sarcoma, neuroepithelioma). We conclude that CD-34 (or a closely related epitope) defines a normally occurring nerve sheath cell that appears to be cytologically and immunophenotypically distinct from a fibroblast and conventional Schwann cell. The antigen can also be localized to benign nerve sheath tumors, but tends to be lost in malignant ones. The consistent presence of CD-34 within all 13 cases of dermatofibrosarcoma protuberans can be used as evidence in support of the view that these lesions are variants of nerve sheath tumors, and distinct from benign fibrous histiocytomas which consistently lack the antigen. Finally, expression of CD-34 by one of three giant cell fibroblastomas reinforces the close relationship between this tumor and dermatofibrosarcoma protuberans.
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The distinction of rhabdomyosarcoma (RMS) from other small blue round cell tumors of childhood, such as Ewing's sarcoma/peripheral primitive neuroectodermal tumor (pPNET) and neuroblastoma, continues to present a diagnostic challenge to pathologists. The recent recognition of the master role of myogenic regulatory proteins in skeletal muscle commitment and differentiation, and the availability of monoclonal antibodies to two of them (myogenin and MyoD1), has prompted us to test their diagnostic utility in routinely processed, formalin-fixed, and deparaffinized tissue. Preliminary studies had demonstrated that, with the use of heat-induced epitope retrieval techniques, expression of myogenin and MyoD1 could be documented specifically in nuclei of fetal skeletal muscle by the respective antibodies. We performed a retrospective immunohistochemical analysis on 72 cases of small blue round cell tumors, including 33 RMSs, 1 metastatic myogenous Wilms' tumor, 26 Ewing's sarcomas/pPNETs, and 12 neuroblastomas. Nuclear expression of myogenin and MyoD1 were both found in 30/33 non-overlapping cases of RMS, with no significant differences in the sensitivity with respect to histological subtypes, and in 1/1 case of myogenous Wilms' tumor. None of the neuroblastomas or Ewing's sarcomas/pPNETs demonstrated positive nuclear staining with either antibody. However, most of the neuroblastomas, and occasional Ewing's sarcomas/pPNETs, showed variable fibrillary, cytoplasmic immunoreactivity with antibody to MyoD1. We conclude that, with the use of microwave-based epitope retrieval, antibodies to myogenin and MyoD1 are both useful markers for the identification of RMS among other small blue round cell tumors of childhood, but antibodies to myogenin have technical advantages over those to MyoD1, as the latter may cross-react with an unknown cytoplasmic antigen in non-muscle cells and tumors.
We report chromosome results from 108 pediatric central nervous system (CNS) tumors. From our data and those in the literature we found that (1) cerebellar and low-grade astrocytic tumors, including gangliogliomas, are most often karyotypically normal; (2) supratentorial tumors were more frequently high-grade tumors that demonstrated a complex karyotype. Chromosome abnormalities were similar to those described in adult astrocytic tumors, namely, +7, 9p abnormalities, and -10; (3) primitive neuroectodermal tumors (PNETs) were virtually always karyotypically abnormal with a high frequency of +7, -8, i(17q), and -22. PNETs with -22 may represent a subset of tumors; (4) typical choroid plexus papillomas showed a normal karyotype, atypical papillomas showed a hyperdiploid karyotype (with +7, +12, and +20), choroid plexus carcinomas showed a hyperhaploid karyotype; (5) a few ependymomas showed hyperdiploidy or hypertetraploidy; (6) germ cell tumors showed complicated karyotypes; (7) monosomy 22 or 22q abnormalities appear to be a recurring finding in the malignant rhabdoid tumors; and (8) meningiomas showed -22 or 22q abnormalities associated with a complex karyotype. In general, in pediatric CNS tumors the least differentiated neoplasms have the greatest number of cytogenetic abnormalities. However, our present morphologic criteria for tumor diagnosis do not always correlate with a consistent karyotype, and further study of pediatric brain tumor morphology, site, behavior, and karyotype is required.
Nestin is an intermediate filament protein (IFP) expressed in undifferentiated cells during CNS development and in CNS tumors. Previous studies have arrived at different conclusions in terms of which types of CNS tumors express nestin. In this report we establish an immunohistochemical protocol using antigen retrieval, which significantly enhances staining with two polyclonal anti-nestin antisera, #130 and #4350. The staining pattern was identical for the two nestin antisera and very similar to that of vimentin, while glial fibrillary acidic protein (GFAP), immunoreactivity was absent from 9.5-week-old forebrain. The current study of 20 primary CNS tumors from pediatric patients included seven ependymomas, seven primitive neuroectodermal tumors (PNETs), five pilocytic astrocytomas, and one glioblastoma multiforme (GBM). All these tumors expressed nestin to various extents, in contrast to five brain metastases tested. Strong nestin immunoreactivity was found in malignant primary CNS tumors, whereas benign pilocytic astrocytomas showed low but consistent nestin expression. In all tumors nestin immunoreactivity was confined to the cytoplasm of tumor cells and was co-expressed with astrocyte markers vimentin, GFAP, and S-100. Vascular endothelial cells of all neoplasms also showed marked immunoreactivity for nestin and vimentin, whereas they were negative for GFAP and S-100. In conclusion, antiserum #4350 detected nestin in formalin-fixed, paraffin-embedded tissue sections by heat-induced antigen retrieval immunohistochemistry. Nestin was expressed in both highly malignant and low malignant gliomas, indicating the potential use of nestin as a diagnostic tumor marker in surgical pathology.
In animal models, the importance of tumor-derived antiangiogenic factors in controlling metastases has been demonstrated by the growth acceleration of distant metastases after surgical excision of a primary tumor mass. We report the case of an infant who developed rapidly growing cutaneous metastases after surgical resection of a neoplasm of an upper extremity. The tumor was undifferentiated, with some morphological features of primitive neuroectodermal tumor. To test the possibility that the primary tumor was secreting an angiogenic inhibitor, cells from the primary tumor were grown in culture, and the culture medium was tested with an in vitro endothelial cell migration assay and Western blot. The cultured cells secreted sufficiently high levels of an angiogenic inhibitor to overcome the inducing ability of vascular endothelial growth factor and basic fibroblast growth factor. One of the secreted proteins was thrombospondin-1, a potent antiangiogenic glycoprotein. The rapid dissemination of distant metastases after resection of the primary tumor in this case suggests that tumor-derived angiogenic inhibitors are important in maintaining the local net balance of angiogenic mediators controlling the growth of micrometastasis.
BACKGROUND: The treatment of malignant brain tumors is hampered by the presence of the blood-brain barrier, which limits chemotherapy penetration to the central nervous system (CNS). In recent years, different strategies have been designed to circumvent this physiologic barrier. The osmotic blood-brain barrier disruption (BBBD) procedure is one such strategy, and has been studied extensively in preclinical and clinical studies. The authors detail their experience so far with the procedure in the context of an open Phase II study in the treatment of malignant brain tumors. METHODS: Patients with histologically proven malignant gliomas, primitive neuroectodermal tumors, primary CNS lymphomas, and metastatic disease to the brain were eligible. Patients enrolled were treated every 4 weeks (1 cycle) for < or = 12 cycles. A methotrexate-based regimen was offered to patients with lymphomas, whereas a carboplatin-based regimen was offered to patients with all other histologies. Before intraarterial chemotherapy infusion, patients were submitted to an osmotic BBBD procedure. RESULTS: Seventy-two patients were included in the current report. The overall median survival times (MST) from treatment initiation for glioblastoma multiforme (GBM), anaplastic oligodendrogliomas, primary CNS lymphomas, and metastases were, respectively, 9.1, 13.9, not reached, and 9.9 months, whereas time to disease progression was 4.1, 9.2, 12.3, and 3.3 months. The MST from diagnosis was 32.2 months for GBM. CONCLUSIONS: These encouraging results prompted the authors to further refine their knowledge of the potential contribution of this procedure in the treatment of brain tumors. These authors designed a randomized Phase III study for patients with GBM that is now open.
An octyl N-acetylglucosaminide derivative with a pentaerythritol chain at position 6 has been synthesized and evaluated as an inhibitor of neural tumor growth. The glycoside inhibited the growth of a neuroectodermic tumor implanted in rats and, when loaded on a slow-delivery polymer disk, caused the destruction of cultured human astroblastoma obtained after surgical biopsy.
Ewing's sarcoma, peripheral primitive neuroectodermal tumors, and Askin tumors are referred to as Ewing tumors (ETs), and are characterized by high MIC2 expression and a t(11;22)(q24;q12) or other rearrangements involving 22q12. In addition to these constant aberrations, facultative numerical and structural aberrations have been reported: gains of chromosomes 8 and 12, the unbalanced translocation t(1;16), and deletions at the short arm of chromosome 1. To evaluate the frequency and to study the biological impact of these facultative aberrations, we analyzed tumor specimens from 58 ET patients by classical cytogenetics and/or in situ hybridization techniques and compared these data with clinical parameters. Gains of chromosomes 8 and 12 were detected in 55% (32/58) and 24% (14/58) of the cases, respectively. Loss of chromosome 16 or der (16)t(1;16) chromosomes were found in 20% (10/51); deletions at 1p36 were observed in 18% (9/51) of the cases evaluated. The presence of these aberrations did not correlate with age and sex of the patients, with the location of the primary tumor or with the extent of disease at diagnosis by chi-square analysis and Fisher's exact test. Patients with tumors harboring gains of chromosome 8 showed a slightly better clinical outcome (n = 14/30, P = 0.17), whereas gains of chromosome 12 did not influence the clinical outcome (n = 7/30, P = 0.63). However, Kaplan and Meier analysis revealed that deletions at the short arm of chromosome 1 were associated with an unfavorable outcome in patients with localized disease (n = 6/22; P = 0.004).
A series of human neuroectodermal tumors, all containing more than the normal diploid DNA, and each with its own distinct chromosome mode, were studied using restriction enzyme cleavage and specific DNA sequence hybridization. Methods described were quite sensitive and quantitative and as few as 40 molecules with a given restriction site were reproducibly detected in total nuclear DNA. Analysis of several fluorescent gel bands associated with different chromosomal domains revealed no changes between any of the tumor and normal cells. Specific probe hybridization, using purified complex repeating sequences, indicated fidelity of base sequence, as well as preservation of the relative amounts of each of a number of minor related multimers in both the tumor and normal cells. Centromeric regions containing arrays of such sequences may be maintained in these tumor cells and furthermore it is possible that some of these cells are polyploid with respect to DNA sequences, rather than aneuploid as their chromosome profiles suggest.
Experimentally induced primitive neuroectodermal tumor (PNET) cell lines were transplanted into neonatal and adult rat brain and examined neuropathologically for their tumorigenic potential. Both cell lines showed a striking migratory behavior in both neonatal and adult brain. Migration of tumor cells was found in host brain parenchyma, along white matter tracts and associated with CSF pathways. These neural tumor cell lines provide a valuable tool for the development of strategies against strongly migrating neural tumors.
Neuroectodermic tumors can mostly be characterized by the presence of tumor-associated glycosphingolipid antigens, such as gangliosides, defined by monoclonal antibodies. Recently, cumulative evidence indicates that gangliosides modify the biological effects of several trophic factors, in vitro and in vivo, as well as the mitogenic signaling cascade that these factors generate. The functional roles of gangliosides in tumor progression can be revisited: (i) ganglioside antigens on the cell surface, or shed from the cells, act as immunosuppressors, as typically observed for the suppression of cytotoxic T cells and dendritic cells, (ii) certain gangliosides, such as GD3 or GM2, promote tumor-associated angiogenesis, (iii) gangliosides strongly regulate cell adhesion/motility and thus initiate tumor metastasis, (iv) ganglioside antigens are directly connected with transducer molecules in microdomains to initiate adhesion coupled with signaling, and (v) ganglioside antigens and their catabolites are modulators of signal transduction through interaction with tyrosine kinases associated with growth factor receptors or other protein kinases. Given the potential importance of these sialylated gangliosides and their modulating biological behavior in vivo, further studies on the role of gangliosides are warranted.
Undifferentiated soft tissue sarcoma (UND-STS) is the most poorly defined tumor eligible for intergroup Rhabdomyosarcoma Studies (IRS). Recent IRS UND-STS experience was reviewed to assess the histologic characteristics and clinical behavior of undifferentiated sarcomas. Of the 1,527 patients entered on IRS-III and IRS pilot-IV, 96 had tumors classified by the IRS Pathology Committee as UND-STS. Of these, 52 had adequate histologic material for this study. After application of immunohistochemistry, 18 tumors were reclassified, mostly as embryonal rhabdomyosarcomas (RMS), primitive neuroectodermal tumors, and intraabdominal desmoplastic small found cell tumors. The remaining 34 UND-STS had a diffuse hypercellular histologic pattern made up of sheets of medium-sized cells. The tumor cells had a minimal to moderate amount of cytoplasm and a variable nuclear morphology, predominately vesicular with finely granular chromatin. Except for reactivity with antibodies against vimentin, most tumors had a negative immunohistochemical profile. The 5 year Kaplan-Meier survival estimate for patients with non-metastatic disease was 72%, a significant improvement when contrasted with patients diagnosed to have UND-STS in IRS-I and IRS-II.
Peripheral neuroepithelioma (PN) can be difficult to distinguish from undifferentiated neuroblastoma (NBL) in the absence of molecular and cytogenetic studies. These primitive neural tumors of childhood are similar in morphology and immunocytochemistry, despite their distinct biochemical and behavioral characteristics. The recently developed monoclonal antibody HBA 71 is specific for the product MIC2, a marker of peripheral primitive neuroectodermal tumors. Because beta 2-microglobulin also is selectively expressed by most tumors in this subset, we examined whether a combination of the antibodies HBA 71 and anti-beta 2-microglobulin could facilitate the differentiation of the two malignancies. We histologically confirmed the diagnoses of 45 paraffin-embedded tumors of presumed neuroectodermal origin (19 PNs and 26 NBLs) from the pathology files of St Jude Children's Research Hospital. Samples were immunohistochemically stained using HBA 71 and anti-beta 2-microglobulin. Molecular and cytogenetic data were correlated with the results in a subset of eight patients. Sixteen (84%) of the 19 PNs reacted with HBA 71 and 13 (76%) of 17 PNs reacted with anti-beta 2-microglobulin. None of the NBLs reacted with either antibody. Three PNs were identified by HBA 71 alone and one was identified by anti-beta 2-microglobulin alone. Cellular genetic findings were consistent with the results. HBA 71 and anti-beta 2-microglobulin, when used in combination, can facilitate the differential diagnosis of PN and NBL.
BACKGROUND: Trilateral retinoblastoma refers to bilateral retinoblastoma associated with an intracranial primitive neuroectodermal tumor in the pineal or suprasellar region. The purpose of this study was to review patient and tumor characteristics and treatment outcome in patients with trilateral retinoblastoma and to determine whether there is a difference in presentation or outcome according to the location of the intracranial tumor. METHODS: A MEDLINE search of all English language articles pertaining to trilateral retinoblastoma published between 1977-1997 was performed. A total of 94 different cases were identified and analyzed. RESULTS: The gender was male in 39 patients (41.5%), female in 50 patients (53.2%), and unknown in 5 patients (5.3%). Family history for retinoblastoma was positive in 44 patients (46.8%), negative in 39 patients (41.5%), and unknown in 11 patients (11.7%). The median age at the time of diagnosis of retinoblastoma was 6 months. The median time interval to the development of an intracranial tumor from the time of diagnosis of retinoblastoma was 21 months. In 78 patients (83.0%) the intracranial tumor was in the pineal region and in 16 patients (17.0%) it was in the suprasellar region. The median time interval from the time of diagnosis of retinoblastoma to the development of a pineal region tumor was 24 months whereas the median time interval for the development of a suprasellar region tumor was 1 month. At 6 months after the diagnosis of intraocular tumors, 6 of 61 children with pineal region tumors and 10 of 14 patients with suprasellar region tumors had developed intracranial disease (P = 0.005). Unilateral intraocular retinoblastoma associated with intracranial tumor was more likely to occur in patients with suprasellar region tumors than pineal region tumors (P < 0.015). The median survival after the diagnosis of an intracranial tumor was 6 months regardless of the location of the intracranial tumor. For patients who received no treatment for the intracranial tumor the median survival was 1 month whereas it was 8 months for those who received treatment. Children who were asymptomatic at the time of diagnosis of the intracranial tumor had a better overall survival than those who were symptomatic (P = 0.002). CONCLUSIONS: The prognosis of children who develop trilateral retinoblastoma is dismal with current treatment strategies. Tumors of the suprasellar region present earlier than tumors of the pineal region after the diagnosis of intraocular tumors. Because patients who were asymptomatic at the time of diagnosis of intracranial disease had a better overall survival than those who were symptomatic, screening for intracranial tumors may be a valuable strategy in the management of patients with bilateral and/or hereditary retinoblastoma. [See editorial on pages 3-5, this issue.]