Medulloblastoma with extensive nodularity: a variant with favorable prognosis.

OBJECT: Some medulloblastomas (MBs) are characterized by extreme nodularity and intranodular nuclear uniformity in a fine fibrillary background. These lesions have also been designated as "cerebellar neuroblastoma." Although numerous reports have been published in which their morphological features have been investigated, only a few studies have been focused on their neuroradiological appearance, biological behavior, and response to therapy. The goal of this study was to gather more information about these lesions. METHODS: The authors present 11 cases of MB with extensive nodularity. Five patients were boys and six were girls; all but one were 24 months of age or younger at diagnosis. Magnetic resonance imaging disclosed a peculiar grapelike architecture in eight cases. Surgical tumor removal was complete in nine cases and partial in one. In the other case a biopsy sample of the tumor was obtained after a preoperative course of chemotherapy. After surgery, two children were treated with radiotherapy alone and one with craniospinal irradiation followed by systemic chemotherapy. Eight patients were treated with chemotherapy only. All the patients in the study are presently alive with a median follow up of 66 months. Eight patients (73%) are in complete remission at 35 to 156 months. Three patients treated with chemotherapy alone postsurgery relapsed; however, all underwent successful retreatment (two with craniospinal irradiation and one with further surgery plus high-dose chemotherapy) and are in complete remission. A review of the literature revealed that patients in 11 of 12 reported cases were younger than 3 years of age and that seven of eight in whom follow-up information was available were alive and well, with survival times ranging from 6 to 84 months. CONCLUSIONS: Medulloblastomas with extensive nodularity represent a variant that is characterized by: 1) occurrence in very young children; 2) a peculiar grapelike appearance on neuroimaging; and 3) an apparently favorable outcome.

Extraventricular neurocytoma with ganglionic differentiation associated with complex partial seizures.

We report an unusual case of extraventricular ("cerebral") neurocytoma with ganglion cells located in the right temporal lobe in a 9-year-old girl with complex partial seizures and precocious puberty. CT showed a calcified mass with central cystic zones. MR imaging showed a markedly hyperintense predominately solid tumor on both T1- and T2-weighted images, without appreciable contrast enhancement. Cerebral neurocytomas are histologically benign and radical surgery is curative; they should be included in the differential diagnosis of temporal lobe tumors in children.

[The morphological assessment of bone marrow infiltration in neuroblastoma]. / Valutazione morfologica dell'infiltrazione midollare nel neuroblastoma.

Bone marrow biopsy is very important in diagnosis and follow-up of children affected by neuroblastoma (NB). Between June 1995 and May 1997 we studied 55 patients with NB stage 4. Specimens were obtained at the diagnosis (in 8 patients) and after chemotherapy (in 55 patients) in order to evaluate the effects of treatment on bone marrow disease. 88% of 343 biopsies were representative versus 99% of 639 aspirates. Of 8 stage 4 patients evaluated at diagnosis, 15/16 biopsies versus 9/15 aspirates were positive. Following chemotherapy, out of 298 evaluable sites examined, 111 biopsies versus 30 aspirates (37 versus 10%) were positive. Of 111 positive biopsies 53 showed a focal pattern (35 differentiated, 18 undifferentiated), while 51 showed a diffuse pattern (18 differentiated, 40 undifferentiated). Our results confirm previous literature data indicating a better efficacy of histology versus morphology in detecting residual bone marrow disease (especially in case of focal differentiated pattern). The recent introduction of a specific monoclonal antibody, called anti-GD2, has improved our capacity to detect minimal residual disease in patients' bone marrow. The inclusion of anti-GD2 immunohistochemistry in our evaluation will possibly increase our overall sensitivity to detect minimal residual disease and may provide information capable to direct the physician's decision into a more rational patient's treatment.

[The identification of minimal residual disease in the bone marrow and peripheral blood in neuroblastoma. The prognostic and therapeutic implications]. / Identificazione della malattia residua minima nel midollo e nel sangue periferico nel neuroblastoma. Implicazioni prognostiche e terapeutiche.

A highly sensitive and specific methodology to detect neuroblastoma cells in the bone marrow and peripheral blood of children with neuroblastoma is of critical importance for proper staging and treatment of these patients. In addition, patients with bone marrow infiltration at diagnosis need to undergo regular investigation to measure the effectiveness of chemotherapy (so called "in vivo" purging). Finally, the evaluation of autologous stem cells taken from bone marrow or peripheral blood is necessary to rule out or minimise the possibility of reinfusing tumor cells to the patient following myeloablative therapy. The authors provide a "state of the art" data on this complicated issue and give their preliminary results of their own experience, mainly concerning the immunocytological methods.

Carcinomalike monotypic epithelioid angiomyolipoma in patients without evidence of tuberous sclerosis: a clinicopathologic and genetic study.

We report the clinicopathologic, immunohistochemical, ultrastructural, and genetic features of an unusual renal tumor composed of large, atypical, densely packed, clear/eosinophilic epithelioid cells. Three patients, two men and one woman (ages 31, 36, and 60 years of age, respectively), had abdominal pain. Morphologically, all cases showed aggressive features (largeness, atypical cells, sarcomatoid features, necrosis, and, in one case, invasion of the renal vein). Despite the marked morphologic resemblance of these tumors to high-grade sarcomatoid renal cell carcinoma, their phenotype (HMB45+, CD68+/-, actin+/-, and vimentin and keratin negative) is in contrast to that observed in epithelial tumors and parallels the phenotypic profile of angiomyolipoma. Ultrastructural analysis showed the presence of glycogen, mitochondria, and prominent electron-dense, membrane-bound granules in the neoplastic cells, and the absence of melanosomes or premelanosomes. Genetic study, performed using polymerase chain reaction from paraffin sections, showed a loss of heterozygosity at the TSC2-containing region on 16p in one case, and on 3p in two cases, showing that multiple genetic alterations are taking place in these tumors. Follow-up has shown local recurrence in one case after 6 years, and the patient died 1 year later of cardiorespiratory failure. The other two patients are well after 26 and 10 months. All three patients were evaluated for signs of tuberous sclerosis, and findings were negative. We suggest that these tumors should be considered close relatives of the angiomyolipoma variants, composed purely of perivascular epithelioid cells. More cases and longer follow-up durations are needed to fully evaluate its prognostic implication.

Follicular cell carcinoma of the thyroid in a child after bone marrow transplantation for acute lymphoblastic leukemia.

Follicular cell carcinoma (FCC) of the thyroid is rarely found during childhood. We report a 12 1/2-year-old girl with acute lymphoblastic leukemia, who developed rapidly growing FCC of the thyroid, 3 years after bone marrow transplantation. The role of chemotherapy in the induction of such secondary tumors after transplantation is discussed, and a proposal for the approach to these patients is suggested.

Multiple inflammatory fibrosarcoma of the abdominal cavity in a child.

Inflammatory fibrosarcoma is a rare condition in childhood. In the abdominal location, its behaviour is often aggressive and potentially metastasizing. We report a case of a 3-year-old female with abdominal inflammatory fibrosarcoma who relapsed after 1 month from radical surgery. Chemotherapy was ineffective, and we registered a brief stabilisation of disease only with alpha-IFN. Our case confirms the potential malignancy of this tumour and its resistance to treatment. It is noteworthy that the therapy with alpha-IFN improved the quality of life in this child for 4 months.

MRI in an unusual case of congenital spinal mesenchymal proliferation.

We report a child aged 2 years presenting with delayed motor development. A thoracolumbar subcutaneous mass was noticed in the first months of life. MRI showed a low conus medullaris, confirmed the presence of the mass and detected a second solid lesion in the intradural space. Surgery confirmed that the two lesions were distinct, as on MRI. The histopathological features were in common with fibrous hamartoma of infancy, giant cell angioblastoma and the "diffuse type" of infantile fibromatosis. The presence of a low conus medullaris associated with a congenital clinical presentation suggested a disontogenetic aetiology.

Is chemotherapy effective therapy for intracranial immature teratoma? A case report.

BACKGROUND: Intracranial immature teratomas (IT) are very rare germ cell tumors (GCT). The value of chemotherapy in their treatment has not been defined. METHODS: A child was referred to our hospital for consultation regarding the need for adjuvant treatment after being operated upon twice (at the age of 7 months and 11 months) for a large supratentorial intracerebral mass. The patient was staged and the tumor specimens reviewed. Histology was that of an IT with no other type of malignant GCT. RESULTS: Considering the age, lack of any sign of residual tumor by computed tomography and magnetic resonance imaging, absence of tumor cells in the spinal fluid or elevation of tumor markers, and based on the reported poor response of such tumors to chemotherapy, a policy of "wait and see" was adopted. One month later, the child presented with a rapidly growing intracranial mass invading the cranial bones on the left side. Chemotherapy consisting of 4 cycles of carboplatin, etoposide, and bleomycin followed by another 4 cycles of ifosfamide, vincristine, and dactinomycin alternating with carboplatin and etoposide, achieved complete remission, and 24 months after discontinuation of treatment, the patient continued free of disease. CONCLUSIONS: This report indicates that chemotherapy may be effective therapy for intracranial IT. In our patient, chemotherapy modified the natural aggressive behavior of this disease and achieved a persistent, complete remission. Given the minimal information available in the literature concerning the response of IT to chemotherapy, this case addresses the issue of whether chemotherapy alone is adequate to treat intracranial germ cell tumors.

Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas.

To investigate the molecular mechanisms of tuberous sclerosis (TSC) histopathologic lesions, we have tested for loss of heterozygosity the two TSC loci (TSC1 and TSC2) and seven tumor suppressor gene-containing regions (TP53, NF1, NF2, BRCA1, APC, VHL, and MLM) in 20 hamartomas from 18 TSC patients. Overall, eight angiomyolipomas, eight giant cell astrocytomas, one cortical tuber, and three rhabdomyomas were analyzed. Loss of heterozygosity at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). Interestingly, a statistically significant preponderance of loss of heterozygosity at TSC2 was observed in the sporadic group (P < 0.01). Among the possible explanations considered, the bias in the selection for TSC patients with the most severe organ impairment seems particularly appealing. According to this view, a TSC2 defect might confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the seven antioncogenes tested showed loss of heterozygosity, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. Finally, the observation of loss of heterozygosity at different markers in an astrocytoma and in an angiomyolipoma from the same patient might suggest the multifocal origin of the second-hit mutation.

Massively diffuse multifocal granulocytic sarcoma in a child with acute myeloid leukemia.

A case of granulocytic sarcoma in an 8-year-old boy with acute myeloid leukemia and t (8; 21) is reported. The case is of interest due to massive extension of the tumor, which may raise different diagnostic difficulties with other solid tumors such as lymphoma, Ewing sarcoma, and soft tissue sarcoma. Furthermore, the tumor was localized in some sites, such as the parotid region and peripheral nerves, which are not usually involved in granulocytic sarcoma. The case points out the diagnostic difficulties with this kind of tumor and appears to contribute to the identification of a subgroup of acute myeloid leukemia with peculiar features, such as M2 morphology with Auer rods, t (8; 21), granulocytic sarcoma and a poor prognosis.

Histopathology of chronic viral hepatitis: guidelines for a revised classification.

Over the last few years a need for reassessment of the classification of chronic hepatitis has emerged in both clinicians who diagnose and treat liver patients and histopathologists who evaluate liver biopsies. The introduction of an aetiologic terminology, the evaluation of inflammatory activity and necrosis (grading) as well as of fibrosis as the equivalents of a stage in the disease appear to be major requirements. Due to the present satisfactory knowledge of the natural history of hepatitis B, there is also a discussion on the advisability of a personalized classification of chronic hepatitis B, i.e. a classification based upon consideration of profiles (or phases) rather than rigid morphological categories. This paper is intended as a guideline with a view to a revised classification of chronic hepatitis.

Gene expression and protein localisation of calcyclin, a calcium-binding protein of the S-100 family in fresh neuroblastomas.

Calcyclin gene, a Ca(2+)-binding protein with homology to S-100, has been found to be expressed at different levels in leukaemic cells and in other tumour cells. We recently reported the expression of the gene in human neuroblastoma (NB) cell lines, and suggested a possible role of calcyclin in cell differentiation. To extend our findings, we investigated the expression of the gene in NB cells induced to differentiate by retinoic acid (RA), using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. Time-course experiments employing LA-N-5 cells showed that calcyclin mRNA appeared 2 h after RA treatment, long before the cells were blocked in the G1 cell-cycle phase and before the neurite-like structures outgrew from the cell bodies. This suggests the involvement of the gene in the early phase of cell differentiation. Furthermore, we investigated mRNA expression in a series of fresh neuroblastomas. NB tumours showed a heterogeneous pattern of calcyclin expression, although calcyclin seemed to be expressed more frequently in cases with a favourable Shimada histology. We also studied the expression of the protein in formalin fixed and paraffin embedded tissues, by using a specific anticalcyclin antibody. The protein was detected in stromal cells which characterise a more mature histological type, and in nerve sheaths, whereas neuroblasts were negative. The tissue that expressed calcyclin protein showed a Schwann-like differentiation and, unlike S-100 protein, calcyclin was expressed in the perineurium.

9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene.

Tuberous sclerosis is an autosomal dominant disease whose characteristic feature is the development of multiple hamartomas in a variety of organs and tissues. Two major loci have been identified so far: TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3. Loss of heterozygosity at 16p13.3-associated markers has been recently observed in hamartomatous lesions of some tuberous sclerosis patients. Here we report the first evidence of loss of heterozygosity at the TSC1 critical region in a giant cell astrocytoma of a familial tuberous sclerosis case. Segregation analysis showed that the 9q34 haplotype lost carried the putative normal TSC1 gene. These data support the hypothesis of both a germline and somatic loss-of-function mutation for the development of tuberous sclerosis hamartomas and suggest a tumor-suppressor-like activity also for the TSC1 gene product. Finally, the possible significance of a second small region of loss of heterozygosity at 9p21, found in the same astrocytoma, is discussed.

Immunohistochemical and genetic characterization of the M Cagliari alpha-1-antitrypsin molecule (M-like alpha-1-antitrypsin deficiency).

BACKGROUND: Genetic alpha-1-antitrypsin (AAT) deficiency may be due to defective secretion, intracellular degradation, or lack of synthesis. Defective secretion results in hepatocytic storage and liver disease. These two events occur only with the common deficiency variant, Z AAT, and with a few rare deficiency variants, called M-like. Hepatocytic storage of AAT (either Z or M-like) can be demonstrated in tissue sections by specific immunostaining with a polyclonal anti-AAT antibody, that recognizes all variants of AAT. A monoclonal antibody capable of selectively and exclusively reacting with Z AAT has been generated and successfully used in both serum and tissue studies. EXPERIMENTAL DESIGN: To determine whether a new M-like variant, M Cagliari, carries a mutation different from Z AAT, we have compared antigenic properties and DNA sequences of the two variants. Liver tissue sections from PiZ and PiM Cagliari patients were stained with both polyclonal anti-AAT and monoclonal anti-Z AAT antibodies. DNAs were polymerase chain reaction-amplified with AAT-specific primers and sequenced. RESULTS: Liver tissue sections from PiZ livers were positively stained with either the polyclonal or the monoclonal antibody. The PiM Cagliari liver sections reacted with the polyclonal antibody, but not with the monoclonal anti-Z AAT, thus indicating a difference in antigenicity from Z AAT. Accordingly, DNA analysis ruled out a Z mutation and revealed a microdeletion in exon II, identical with M Malton. CONCLUSIONS: A simple immunohistochemical assay based upon the application of both polyclonal and monoclonal antibodies represents a reliable test to distinguish Z and nonZ AAT deficiencies, thus assisting in the selection of cases worthy of more time-consuming analyses such as DNA sequencing. The same approach may be used for the characterization of as yet undefined PiM cases with AAT liver storage.

Congenital bilateral juvenile granulosa cell tumor of the ovary in leprechaunism: a case report.

We report on a case of leprechaunism. In addition to the typical clinical and biochemical features, a bilateral juvenile granulosa cell tumor of the ovaries and cytomegalovirus hepatitis were found. The granulosa cell tumor may result from the mitogenic effect of insulin at high concentration, which acts via a mechanism mediated by insulin-like growth factor I receptors.

N-myc gene amplification/expression in localized stroma-rich neuroblastoma (ganglioneuroblastoma).

Using nucleic acid analysis and in situ hybridization we have demonstrated N-myc amplification and expression in two children with a localized (stages I and II) stroma-rich neuroblastoma (NB) (ganglioneuroblastoma). The phenomenon was observed in both undifferentiated and mature ganglion-like cells. The two children are alive and disease-free without any treatment after 16 and 17 months. These observations suggest that morphologic differentiation in NB in vivo is not necessarily followed by a decrease in N-myc expression. Moreover, N-myc amplification does not represent an adverse prognostic factor. In contrast with what happens in undifferentiated NB, N-myc amplification does not have an adverse effect on prognosis when occurring in localized (stages I and II), stroma-rich NB with a favorable histology.