von Recklinghausen's disease was first described in 1882. Formerly, it was considered a single disease, but is now known to be two distinct disease, neurofibromatosis 1 (NF 1, peripheral form of neurofibromatosis) and neurofibromatosis 2 (NF 2, bilateral acoustic neurofibromatosis). Neurofibromatosis is inherited as an autosomal dominant with a high rate of penetrance. NF 1 gene is located in the pericentromeric region of chromosome 17. NF 2 gene is localized to chromosome 22. Clinically, there are some characteristic signs and symptoms. The typical NF 1 patient has café-au-lait spots, melanin pigmentation and palpable neurofibromas, while NF 2 has its onset with the development of tinnitus or hearing loss, due to the presence of bilateral acoustic neuroma.

Neuroblastoma (NB) is a common malignant solid tumor in childhood, accounting for about 40% of the solid children's neoplasms on the Japanese registry in 1993. It is known that some cases of NB are hereditary, but their incidence is very low. We report two patients with adrenal familial NBs and review the literature on familial NB. Two hit theory was proposed to explain the occurrence of hereditary and non-hereditary NBs. This theory supports the fact that the median age at diagnosis is much younger and the incidence of multiple primaries is higher in the familial NB than in non-familial cases. As therapy for NB improves and more children survive to adulthood, there will be more opportunity to study their offspring.

Recent advances in molecular genetics have disclosed oncogenes playing a significant role in the development of malignant gliomas. Amplification of the c-erb gene which code EGFR and aberration of P53 oncogene play a significant role in the development of most malignant gliomas. Karyotype analysis of malignant gliomas revealed gains of chromosome 7, loss of chromosome 10, double minutes and loss of heterozygosity. The development of the tumors appear to result from the accumulation of those multiple genetic alterations. Although many cases of familiar malignant gliomas have been reported the role of hereditary factors in familial transmission still remains controversial. Chromosomal abnormalities seemed to be confined to the tumor cell, and no alteration in karyotype of peripheral blood, which indicated germ line mutation, was demonstrated. However, several authors indicated that the frequency of malignant gliomas in the relatives of patients was estimated more than ten times to the controls. Some hereditary factors might play a role in malignant gliomas.

Intracranial hemangioblastoma (Lindau's disease) is vascular-rich benign neoplasm, arise from vascular endothelium. They account for about 2-3% of all intracranial tumors. Its most common location is adult posterior fossa. Except for the cerebellum, they were sometimes found in the brainstem or spinal region. Common macroscopical findings is mural nodule with cyst in the cerebellum. Contrary, solid form is common in spinal and brainstem region. The lesions are readily identified by image diagnostic procedures. Intracranial hemangioblastoma associated with retinal hemangioblastoma is called "von Hippel-Lindau's disease", hereditary disease of autosomal dominant form with chromosome abnormalities of 3p25-26. In other particular type of "von Hippel-Lindau's disease", intracranial hemangioblastomas are associated with renal cell carcinoma, pancreatic cyst or pheochromocytoma sometimes without retinal hemangioblastoma. Surgical extripation is the best choice of treatment for this disease. However, brainstem or spinal hemangioblastomas are sometimes difficult to remove totally.

The methods for the detection and the identification of tumor suppressor genes are characterized and classified as follows: Firstly; by the comparison of expressed genes or proteins between tumor cells and normal cells. Secondly; by the gene transfer. Thirdly; by the identification of proteins which are involved in the biochemical process for cell growth suppression and DNA repair. Human genome contains dozens of tumor suppressor genes and tumor suppression-related genes which have not yet been cloned. Positional cloning is the most reliable method for the cloning of these genes. However, it cost huge amount of labor and time. New methods developed in recent years, such as differential mRNA display or two hybrids system, would facilitate the identification and the molecular cloning of novel tumor suppressor genes.

Linkage analysis using polymorphic DNA markers have played significant roles in identification of genes related to development of cancer. The genes associated with hereditary cancer syndromes are divided into three classes, oncogenes, tumor suppressor genes, and genes related to the DNA repair system. The majority of these genes have been isolated through the mapping of the disease loci by linkage analysis of a large number of affected kindreds. I summarize here the principle of linkage analysis as well as a history of polymorphic DNA markers, RFLP (restriction fragment length polymorphism), VNTR (variable number of tandem repeat), and microsatellite markers.

Hereditary cancers have been shown to develop through at least two mechanisms. Development of retinoblastoma and Wilms' tumor is usually not accompanied by other hereditary symptoms. Although they are inherited autosomal dominantly, gene mutations in recessive tumor suppressor genes were found to be responsible for these tumors. The other mechanism is the enhanced mutation in the cancer-prone hereditary diseases, such as xeroderma pigmentosum, Bloom's syndrome, etc. In xeroderma pigmentosum, for example, defects in DNA repair has been shown to enhance the frequency of mutation in the oncogenes and tumor suppressor genes. Recently, another repair-related mechanism, involving the mismatch repair, was found to be involved in the hereditary nonpolyposis colon cancer.

Hereditary cancer syndrome and some recessibly inherited diseases with increased predisposition to cancer are reviewed with special reference to their recent concept and classification. That tumor suppressor genes and some oncogenes are of potential relevance to their development is discussed.

Fluorescence in situ hybridization was done with specimens obtained by bronchial brushing from 25 patients with abnormal lung shadows. A satellite DNA probe, specific for chromosome 11, was used to detect numerical chromosome aberrations in tumor cell nuclei. Normal diploid human lymphocyte nuclei, which served as control, had two signal spots in 99.6% of the nuclei in response to the chromosome 11 probe. The most frequent signal spots in class V cells (Case 1-7) ranged from 3 to 5, followed by 6 to 8, regardless of histopathological findings of lung cancer. In class I cells (cases 8-11) the signal appearance was similar to that in class V cells. The disease in patients from whom class I cells were obtained was found to be malignant by other diagnostic procedures performed afterward. The abnormalities in cases 13-25 were diagnosed as non-malignant by brush cytology, and clinical course showed a little more than 3 spots. These data indicate that fluorescence in situ hybridization with specimens obtained by bronchial brushing can be useful for detecting numerical chromosome abnormalities and can aid in the rapid diagnosis of lung cancer.

The first report of the familial testicular cancers in a father and his son in Japan was presented. The father had right testicular seminoma at 41 years of age and his son had right testicular embryonal cell carcinoma associated with teratoma elements at 17 years of age. To date only 30 pairs of testicular cancers occurring in father and son have been reported worldwide. Survey of the literature suggested that hereditary factors might be involved in the familial occurrence of testicular cancers although there was no definitive evidence.

A 39-year-old male was referred to our hospital in June, 1993, because of leukocytosis. Physical examinations showed massive splenomegaly without any lymphadenopathy. The white blood cell count was 13,800/microliters with 87% morphologically mature lymphocytes. Bone marrow aspirate revealed hypercellularity with 67% lymphocytes morphologically similar to peripheral lymphocytes. The lymphocytes displayed monoclonal rearrangements of immunoglobulin genes and the phenotype of CD5-CD19+CD20+ CD21+ and Smlg+. Splenectomy was effective against neutropenia and thromboytopenia. The clinical and laboratory findings of this case were unusual compared to those of typical B-CLL in massive splenomegaly, no lymphadenopathy and CD5-phenotype, suggesting the heterogeneity of B-CLL.

We report a 3-year-old boy with acute myelogenous leukemia, who relapsed very early after peripheral blood stem cell transplantation (PBSCT). He was admitted with a tumor in maxillar sinus and hemorrhagic diathesis and was diagnosed as having acute myelogenous leukemia with t(8;21). He achieved complete remission with etoposide, cytosine arabinoside and mitoxantrone. After 8 courses of consolidation therapy and marrow ablative chemotherapy, he received PBSCT. G-CSF was given from day 0 because of severe infection. WBC and platelete counts rapidly increased, however, from day 20 platelet count spontaneously decreased. Concomitantly bone marrow examination revealed the presence of blastic cells. RT-PCR showed that the presence of AML 1/MTG 8 chimera mRNA in the cryopreserved PBSC samples. In vitro analysis also revealed that leukemic cells had G-CSF receptors and increased 3H-thymidine uptake in the presence of G-CSF. These findings strongly suggest that the reinfusion of leukemic cells in PBSC and the administration of G-CSF after PBSCT might be relevant to early relapse in this patient.

A 49-year old man was admitted in November 1989, because of anemia, abnormal shadowing on chest X ray and hyperproteinemia. Biclonal gammopathy (IgG kappa + IgA kappa) was shown in serum, and Bence Jones protein in urine. The bone marrow examination showed an increased number of abnormal plasma cells (15.7%) and no evidence of lymphoma, A diagnosis of multiple myeloma (MM) was made. In April 1990, while the patient was treated with the modified M2 regiman, swelling of the right cervical lymph node was observed. Lymph node biopsy revealed that he had non-Hodgkin's Lymphoma (:NHL, diffuse, mixed, B cell type). He was retreated with the CHOP regimen for both disease, but died of respiratory failure in October. 1991. To establish the clonal origin of this case of concominant MM and B-cell NHL, the immunoglobulin gene rearrangements in his lymph node and bone marrow were analyzed. Southern blot analysis with the JH probe and Ck probe showed one common band and one different band in the two samples. Our data suggest that two B-cell malignancies may have arisen from a single B-cell progenitor.

A 55-year-old patient with multiple myeloma (IgG-lambda) diagnosed in November 1988 was admitted because of bone pain throughout the body. After plasmapheresis and several courses of chemotherapy, a massive tumor of the left thoracic wall involving the rib appeared. Radiotherapy was performed to ameliorate the severe chest pain, after which myelomatous pleural effusion appeared on the left side. The serum, urine and pleural effusion revealed increased activity of amylase of the salivary type. Amylase activity was also detected in the supernatant of myeloma cells cultured from pleural effusion. We reviewed 12 cases of ectopic amylase-producing multiple myeloma. All the cases except one have been reported from Japan, and hyperamylasemia in these cases was detected at diagnosis or during course of the illness. Moreover, cytogenetic analysis of myeloma cells of previous reports revealed structural abnormalities including chromosome 1, near the amylase gene locus. This case also showed t (1; 10) (q 21?; q 26) by examination of 8 metaphase derived from bone marrow. These observations suggested that ectopic amylase production was induced by irradiation to the plasmacytoma of thoracic wall.