Cancer history and loss of MSH2 and MLH1 protein expression in patients with endometrial hyperplasia.

In order to evaluate the hereditary background of endometrial hyperplasia patients in relation to protein expression of DNA mismatch repair genes, we evaluated 69 patients with endometrial hyperplasia and 18 patients with normal endometrium having both a personal and family history of cancer (two hereditary nonpolypoid colorectal cancer (HNPCC) patients). We obtained personal and family histories of cancer for all patients. MSH2 and MLH1 protein expression was investigated by immunohistochemical methods. In the endometrial hyperplasia patients, 11 had personal histories and 40 had family histories of cancer. Among the 11 endometrial hyperplasia patients with a personal history of cancer, most cancers were breast or colorectal cancers (82%). In the 40 patients with a family history of cancer, colorectal cancer (33%) was the most frequent. The incidence of loss of expression of MSH2 and/or MLH1 protein in endometrial hyperplasia patients with personal (64%) or family (40%) histories was significantly higher than that in patients without such history (no personal: 21% and no family: 10%; P = 0.0035 and 0.0065). No protein loss was detected in any of the cases with normal endometrium having either a personal or family history of cancer. Our results suggest that a portion of endometrial hyperplasia cases having a personal or family history of cancer may belong to HNPCC, and that in these cases, abnormality of the mismatch repair system may be an early event in endometrial carcinogenesis.

A possible role of VEGF in osteolytic bone metastasis of hepatocellular carcinoma.

The incidence of bone metastasis was around 13% in 404 patients with hepatocellular carcinoma (HCC) who underwent treatment at the National Kyushu Cancer Center between 1988-97, which is a high value among various cancers. This is, in part, due to the prolonged survival time of HCC patients in recent years. Serum vascular endothelial growth factor (VEGF) levels were significantly elevated in HCC patients with bone metastases as compared to those in patients with liver cirrhosis/chronic hepatitis and HCC patients without bone metastasis. VEGF was positively stained in both the primary lesion and bone metastasis of HCC by immunohistochemistry. In the process of bone metastasis, an increase in bone resorption is a crucial step prior to invasion of the bone. VEGF, the most important angiogenic factor, has been shown to stimulate bone resorption through its effects on osteoclasts. Thus, HCC cells reach the bone marrow space, and then secrete VEGF which facilitates osteolytic bone metastasis. VEGF may also facilitate tumor growth in the bone by acting as an angiogenic factor once invasion of the bone is complete. This might be another reason for the high incidence of bone metastasis in HCC.

EGFR, c-erbB2 and p53 protein in the primary lesions and paired metastatic regional lymph nodes in breast cancer.

AIMS: Various biological parameters are now being evaluated as predictors for the response of chemohormonal therapy for breast cancer. Few studies compare these parameters between the primary lesions and metastatic regional lymph nodes of breast cancer. METHODS: Immunohistochemical analyses for epidermal growth factor receptor (EGFR), c-erbB2 and p53 protein were performed on the primary lesions and matching metastatic regional lymph nodes of 107 breast cancers. The intensity of the immunoreactivity was graded for heterogeneous or 10-50% staining, and diffuse or >50% staining. RESULTS: EGFR, c-erbB2 and p53 protein showed a concordance between the primary lesions and matching regional lymph nodes in terms of a negative or positive finding (+ and ++) in 98 (92%) of 106 cases, 76 (100%) of 76 cases and 79 (93%) of 85 cases respectively, while EGFR, c-erbB2 and p53 protein also showed a concordance in the intensity of the immunoreactivity in 24 (89%) of 27 cases 14 (74%) of 19 cases and 30 (94%) of 32 cases respectively. In 21 of 24 cases which showed a disconcordance in the positivity or the intensity of the positivity of EGFR, c-erbB2 and p53 protein, one of the primary lesions and matching regional lymph nodes showed heterogeneous or 10-50% immunostaining. CONCLUSIONS: The immunoreactivity of EGFR, c-erbB2 and p53 protein shows a concordance between the primary lesions and matching metastatic regional lymph nodes in a majority of breast cancers.

International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group.

BACKGROUND: The International Neuroblastoma Pathology Classification was established in 1999 for the prognostic evaluation of patients with neuroblastic tumors (NTs). METHODS: Pathology slides from 746 NTs (the Children's Cancer Group [CCG]-3881 and CCG-3891 studies) were evaluated according to the International Classification. First, prognostic effects of the morphologic indicators (grade of neuroblastic differentiation: undifferentiated [U], poorly differentiated [PD] and differentiating [D]; and mitosis-karyorrhexis index [MKI]: low [L-MKI], intermediate [I-MKI], and high [H-MKI]) for tumors in the neuroblastoma (NB) category were tested. Then, prognostic significance of the International Classification for all NTs in four categories (neuroblastoma [NB]; ganglioneuroblastoma, intermixed [GNBi]; ganglioneuroma [GN]; and ganglioneuroblastoma, nodular [GNBn]) was analyzed. Finally, age distribution of the patients in the four categories as well as three subtypes (based on the grade of differentiation) in the NB category was compared. RESULTS: There were 630 NB tumors, 30 GNBi tumors, 10 GN tumors, and 76 GNBn tumors. In the NB category, prognostic effects of the indicators (three grades of differentiation and three mitosis-karyorrhexis index [MKI] classes: low [L], intermediate [I], and high [H]) were affected significantly by the age of the patients. The age-linked evaluation of the indicators according to the International Classification successfully distinguished two prognostic subgroups: the favorable histology (FH) subgroup (PD/D and L/I-MKI tumors in patients age < 1.5 years, D and L-MKI tumors in patients ages 1.5-5.0 years; 90.4% 5-year event free survival [EFS]) and the unfavorable histology (UH) subgroup (U and/or H-MKI tumors in patients of any age, PD and/or I-MKI tumors in patients ages 1.5-5.0 years, any grade of differentiation, and any MKI class in patients age > or = 5 years; 26.9% EFS) (P < 0.0001). The International Classification also distinguished the FH group (FH subgroup with NB, GNBi, and GN tumors) and the UH group (UH subgroup with NB and GNBn tumors) for all NTs (90.8% EFS and 31.2% EFS, respectively; P < 0.0001) and provided independent prognostic information on both patient age and disease stage (P < 0.0001). Among patients with FH tumors, the median ages of patients with the PD and D subtype tumors in the NB category were 0.43 years (range, 0-1.50 years) and 1.50 years (range, 0.02-4.65 years), respectively, and the median ages of patients with GNBi and GN tumors were 3.51 years (range, 0.96-14.85 years) and 4.80 years (range, 1.94-17.05 years), respectively. In contrast, patients with UH tumors generally were older when they were diagnosed, and with median ages of 2.99 years (range, 1.30-8.84 years) for patients with U subtype tumors, 2.59 years (range, 0.0-12.57 years) for patients with PD subtype tumors, 2.16 years (range, 0.35-9.90) for patients with D subtype tumors, and 3.26 years (range, 0.57-15.90 years) for patients with GNBn tumors. CONCLUSIONS: This study confirmed the prognostic significance of the International Classification, substantiated age-linked prognostic effects of the morphologic indicators for patients with the tumors in the NB category, and supported the concept of an age-appropriate framework of maturation for patients with the tumors in the FH group.

Prognostic value of DNA ploidy in 653 Japanese women with node-negative breast cancer.

BACKGROUND: The prognostic value of DNA ploidy has been extensively studied in breast cancer; however, the results remain controversial. Flow cytometry (FCM) studies of DNA ploidy on frozen sections have not yet been performed in a large series of Japanese women with node-negative breast cancer. METHODS: An FCM analysis of DNA ploidy was performed on frozen sections of node-negative breast cancer from 653 Japanese women, with a mean follow-up duration of 46 months. RESULTS: Three hundred and twenty-four (49.6%) patients showed a diploid tumor, while 329 (50.4%) showed an aneuploid tumor. There was a significant correlation between DNA ploidy and estrogen receptor (ER) status. Patients with an aneuploid tumor had a significantly worse outcome in terms of both disease-free survival (DFS; P = 0.0116) and overall survival (OS: P = 0.0492) than those with a diploid tumor, while the same effect, in terms of DFS, was also seen in ER-positive breast cancer. Multivariate analyses indicated DNA ploidy to be an independent prognostic factor for DFS, while DNA ploidy and tumor size were found to be independent prognostic factors for OS. DNA ploidy was also shown to be an independent prognostic factor for DFS in ER-positive breast cancer. CONCLUSION: Our findings demonstrated DNA ploidy, based on FCM, to have an important prognostic value in Japanese women with node-negative breast cancer.

Prognostic value of p53 protein expression in breast cancer; an immunohistochemical analysis of frozen sections in 514 Japanese women.

BACKGROUND: Although the prognostic value of p53 protein has been extensively studied in breast cancer, there have so far been few immunohistochemical studies of p53 protein using frozen sections in a large series of Japanese women with breast cancer. PATIENTS AND METHODS: Immunohistochemical staining for p53 protein was performed on frozen sections from 514 Japanese patients with breast cancer with a mean follow-up duration of 31 months. RESULTS: Two hundred and eight (40.5%) of 514 cases showed nuclear accumulation of p53 protein. There was a significant inverse correlation between p53 protein and estrogen receptor (ER) status. The patients who were positive for p53 protein had a significantly worse outcome in terms of both disease free survival (DFS) (p<0.0001) and overall survival (OS) (p=0.0411) than those negative for p53 protein. The same effect on DFS was seen in subgroups divided either by nodal status or ER status. Multivariate analyses indicated that nodal status, ER and p53 protein were all independent prognostic factors for DFS. The nodal status, ER and tumor size were independent prognostic factors for OS, and p53 protein status was still an independent prognostic factor for DFS in subgroups divided either by nodal status or ER status. CONCLUSION: Our findings demonstrated the prognostic value of p53 protein expression for the early recurrence of breast cancer, and the prognostic value of p53 protein expression was independent from that of both the nodal status and ER status in breast cancer.

Pleomorphic leiomyosarcoma: clinicopathologic and immunohistochemical study with special emphasis on its distinction from ordinary leiomyosarcoma and malignant fibrous histiocytoma.

Pleomorphic leiomyosarcoma (PLMS) was recently described as a morphologic variant of leiomyosarcoma; however, its diagnostic criteria, as shown by morphologic features and biologic behavior, remain controversial. We describe 28 cases of pleomorphic sarcoma with pleomorphic areas in more than two thirds of the tumor and an ordinary leiomyosarcomatous fascicular area covering less than one third as PLMS. PLMS comprised 8.6% of all the leiomyosarcomas (322 cases) registered in our institute. Patients ranged in age from 31 to 89 years (average, 57.9 years). Seventeen patients (60.7%) were male and 11 were female. Tumor location was as follows: the extremities in 17 cases, the retroperitoneum or abdominal cavity in 7 cases, the chest/abdominal wall in 3 cases, and the scalp in 1 case. Histologically, all cases showed at least small foci of fascicles consisting of smooth muscle tumor cells, in addition to pleomorphic areas mimicking storiform-pleomorphic malignant fibrous histiocytoma. The border between pleomorphic and leiomyosarcomatous fascicular areas was sharp in 3 cases, gradual in 2 cases, and blending in 23 cases. Sixteen cases (57.1%) showed a typical storiform pattern, 6 cases revealed extensive stromal hyalinization, 6 cases showed a chronic inflammatory infiltrate, 2 cases had the foci of foamy xanthomatous cells, and 7 cases contained myxoid malignant fibrous histiocytoma-like areas covering less than 50% of the tumor. The tumors had a tendency to be of a morphologically higher grade (10 tumors were French Federation of Cancer Centers grade 2, 18 were grade 3). Five of 28 cases (18%) showed rhabdoid features. Immunohistochemically, all of the 28 tumors examined showed a positive reactivity for at least one smooth muscle marker (desmin, muscle-specific actin, and alpha-smooth muscle actin) in the leiomyosarcomatous fascicular areas. In the pleomorphic areas the expression of smooth muscle markers (desmin 10 of 28, muscle-specific actin 13 of 28, and alpha-smooth muscle actin 14 of 28) was significantly reduced, compared with that in leiomyosarcomatous fascicular area (desmin 18 of 28, muscle-specific actin 26 of 28, and alpha-smooth muscle actin 24 of 28). No significant difference was observed between the MIB-1 labeling index in the leiomyosarcomatous fascicular areas (26.10 on average) and that in the pleomorphic areas (26.17 on average). However, the MIB-1 labeling index in PLMS was significantly higher than that in ordinary leiomyosarcoma (n = 20, 12.86 on average) or storiform-pleomorphic malignant fibrous histiocytoma (n = 16, 16.63 on average). In 23 patients follow-up data were available with a duration of 1-239 months. Eleven patients developed metastases, and lung accounted for the most common site of metastasis (9 cases). Fifteen of 23 patients (65.2%) died of disease. Our results indicate that PLMS should be differentiated from ordinary leiomyosarcoma because of its high proliferative activities and rather aggressive biologic behavior.

Expression of intercellular adhesion molecules in epithelioid sarcoma and malignant rhabdoid tumor.

We clinicopathologically evaluated 31 cases of epithelioid sarcoma (ES; 25 'classical' type and six 'proximal variant' type) and six cases of malignant rhabdoid tumor (MRT; three extrarenal and three renal). We also did immunohistochemical studies on 12 classical and three proximal variant cases of ES, and six cases of MRT, to clarify the differences in biological behavior in these tumors. E-cadherin, beta-catenin and CD34 expression was evaluated. We also carried out mutational analysis of exon 3 of the beta-catenin gene by polymerase chain reaction-single-strand conformation polymorphism analysis. In ES, the 5- and 10-year survival rates were 71.1 and 55.3%, respectively. A high mitotic rate (>15/10 high-power fields) was significantly correlated with a poor overall survival rate in ES (P = 0.0248). E-cadherin expression was observed in nine cases (69.2%) of ES and in four cases (66.7%) of MRT. Most of these tumors showed aberrant E-cadherin expression. Seven cases (46.7%) of ES were positive for CD34, although none of the cases of MRT were CD34 positive. Eleven cases (73.3%) of ES were positive for beta-catenin, which was localized to the cellular membrane, whereas all of the cases of MRT were beta-catenin negative. Mutational analysis for the beta-catenin gene was done in nine cases of ES and six cases of MRT, however, genetic alteration was not found. From our results, we conclude that beta-catenin membranous expression could be a useful marker for distinguishing ES, including the proximal variant, from MRT.

Mutations of the p53 gene in malignant rhabdoid tumors of soft tissue and the kidney: immunohistochemical and DNA direct sequencing analysis.

Malignant rhabdoid tumor (MRT) is characterized by the presence of intracytoplasmic eosinophilic inclusions composed of whorls of intermediate filaments. This tumor was originally described as an entity of the abortive type of Wilms' tumor in childhood. Recently, it has been proved that these rhabdoid cells can be observed in various types of malignant tumors, including soft tissue sarcoma or carcinoma. To investigate the oncogenesis of this tumor, we examined the p53 gene alteration by means of immunohistochemical analysis and DNA direct sequencing in three cases of malignant rhabdoid tumor (MRT) of the soft tissue and three cases of MRT of the kidney. All the cases of MRT of the soft tissue and two of the cases of MRT of the kidney showed immunopositivity for p53 protein. Among them, one of the cases of MRT of the soft tissue and two of the cases of MRT of the kidney showed missense mutations of the p53 gene. These results strongly suggest that p53 gene alterations may have an important role to play in the aggressive biological behavior and poor prognosis of this tumor.

Nonfunctioning adrenal rest tumor of the liver: radiologic appearance.

We describe the radiologic features of an adrenal rest tumor of the liver. The adrenal rest tumor appeared on ultrasound as a round, well defined, heterogeneous, solid mass in the posterior aspect of the liver, on angiography as a homogeneous hypervascular mass, and on dynamic CT as a mass containing components of both fat density and soft tissue density and showing early fill-in and early fill-out. Adrenal rest tumors should be included in the lists of hypervascular or fat-containing masses in the liver.

Histopathological Predictors of Axillary Lymph Node Metastases in Patients with Breast Cancer.

BACKGROUND: A tumor 30 mm or less in diameter is a standard candidate for breast conserving surgery (BCS) in Japan. Axillary lymph node metastases (ALNM) is the most important prognostic factor for survival in patients with breast cancer, but the role of axillary node dissection has been controversial. Histopathological predictive factors of axillary lymph node involvement have not been established. The purpose of this study was to determine the association between the incidence of ALNM and histopathological factors by univariate and multivariate analysis METHODS: Sixty-five patients with noninvasive ductal carcinoma, and 993 patients with tumors 30 mm or less in diameter who underwent axillary dissection between 1988 and 1997 at our institute were reviewed. The association between ALNM and 13 histopathological factors (size, age, histological subtype, histological invasiveness, lymphatic invasion, vascular invasion, macroscopic classification, histological daughter mass, ductal spread, ER, PgR, p-53, and c-erbB-2) were analyzed by univariate and, when significant, by multivariate analysis. RESULTS: Only one patient with noninvasive ductal carcinoma had ALNM, and 33.1% of 993 patients with a tumor 30 mm or less in size had ALNM. Multivariate analysis identified six factors as independent predictors for ALNM: lymphatic invasion, size, histological invasiveness, macroscopic classification, age and histological daughter mass. CONCLUSION: Axillary lymph node dissection can be omitted in patients with noninvasive ductal carcinoma. Histopathological features of tumors 30 mm or less in diameter can be used to estimate the risk of ALNM, and routine axillary node dissection might be spared in selected patients at minimal risk of ALNM, if the treatment decision is not influenced by lymph node status, such as in elderly patients.

Development of unfavorable hepatoblastoma in children of very low birth weight: results of a surgical and pathologic review.

BACKGROUND: The incidence of hepatoblastoma in children of very low birth weight (< 1500 g) is increasing in Japan. The authors reviewed surgical and pathologic aspects of the tumor to clarify the characteristics of the patients. METHODS: Fifteen patients (9 boys and 6 girls) who were diagnosed between the ages of 6-77 months (median, 16 months) were identified from the data in the Japan Children's Cancer Registry and the data base of medical journals. The patients' birth weights ranged from 560-1380 g (median, 826 g) and the gestational age ranged from 23-33 weeks (median, 25 weeks). The medical records of all patients were reviewed and the patient's stage of disease according to the classification of the Japanese Society of Pediatric Surgeons, treatment, and outcome were analyzed. RESULTS: Ten tumors (67%) were classified as Stage II or IIIA and 5 (33%) were classified as Stage IIIB or IV. There was a significant correlation between the gestational age and tumor stage (correlation coefficient - 0.6851; P = 0.0048). The gestational age of the 5 patients with Stage IIIB or IV tumors was 23-25 weeks (median, 24 weeks), whereas it was 25-33 weeks (median, 27.5 weeks) for the 10 patients with Stage II or IIIA tumors (P = 0.0036). Birth weight ranged from 560-826 g (median, 734 g) in Stage IIIB and IV patients, which was significantly lower than that in Stage II and IIIA patients (range, 607-1380 g, median, 909 g; P = 0.0500). Complete tumor resection was achieved in 7 patients (47%). The actuarial 2-year survival of all patients was 0.42, and the 2-year survival of patients who underwent complete tumor resection was 0.69, which was significantly better than the 2-year survival of those who underwent incomplete resection (0.17; P = 0.0211). The 2-year survival of the patients with tumors of well differentiated histology was 0.60, which also was significantly better than the 2-year survival of those with tumors of poorly differentiated histology (0.19; P = 0.0453). CONCLUSIONS: These results indicate that children of very low birth weight (< 1500 g) are at high risk of developing advanced hepatoblastomas and that hepatoblastoma with unfavorable biologic behavior develops in children who are extremely premature at birth. These new findings suggest the presence of etiologic factors relevant to the patient's immaturity and the development of unfavorable hepatoblastoma.

N-myc gene amplification in rhabdomyosarcoma detected by fluorescence in situ hybridization: its correlation with histologic features.

Fluorescence in situ hybridization (FISH) was applied to 15 alveolar rhabdomyosarcomas (A-RMSs) and 14 embryonal RMSs (E-RMSs) to detect N-myc (also called MYCN) oncogene amplification. The results were compared with histologic characteristics and clinical factors. The number of surviving patients in each subtype was 5 of 15 with A-RMS and 5 of 14 with E-RMS. N-myc amplification was detected in 9 of the 15 A-RMSs but in none of the 14 E-RMSs. Tumor cells exhibiting N-myc amplification were identified only in the alveolar area in two A-RMSs, and they demonstrated a histologic mixture of alveolar and embryonal patterns. The remaining seven cases with an amplified N-myc showed a conventional alveolar pattern. Among the 15 A-RMSs, the survival rate of patients with tumors showing nonamplified N-myc and amplified N-myc oncogene was 4 (66%) of 6 and 1(11%) of 9, respectively (P < .05). No significant difference was observed between the other clinical findings (age, primary sites, clinical stages) of the N-myc-amplified and nonamplified tumors. Therefore, we concluded that the N-myc gene amplification, which is characteristic of a particular subtype of A-RMS, might be useful as a prognostic factor for an unfavorable outcome.

Application of fluorescence in situ hybridization to detect N-myc (MYCN) gene amplification on paraffin-embedded tissue sections of neuroblastomas.

Fluorescence in situ hybridization (FISH) was applied to neuroblastoma for detection of N-myc (MYCN) oncogene amplification, and the results were compared with Southern blot analysis (Southern). In nine neuroblastomas (formalin-fixed paraffin-embedded tissues were available in seven cases including two cases with touch preparations, and two cell lines), all five cases with N-myc amplification detected by Southern had cells with multiple N-myc signals by FISH, and three cases showed no N-myc amplification either by Southern or FISH procedure. One case, not examined by Southern, showed amplified signals of N-myc by FISH. These data indicate that FISH results for N-myc amplification have close correlation with Southern blot analysis. The chromosome 2-specific repetitive DNA probe was also applied for the analysis of ploidy by FISH. Six cases with N-myc amplification by Southern and/or FISH had diploid tumors and two cases without amplified N-myc showed aneuploidy. The remaining one case consisted of heterogeneous elements showing diploidy in undifferentiated tissue and both aneuploidy (ganglionic cells) and diploidy (Schwann cells) in differentiated area. We conclude that FISH is a practical, useful and reliable method over Southern especially for analysis of N-myc amplification in neuroblastoma, and simultaneous cohybridization with a specific chromosome probe is of great value in predicting the prognosis of patients.

Stage IVS neuroblastoma: a clinical, histological, and biological analysis of 45 cases.

This study reports clinicopathologic and biological analysis of 45 stage IVS neuroblastomas (IVS-NBs). All IVS-NB cases had small or undetectable primary tumors associated with disease involving the liver, skin, or bone marrow. Their ages at diagnosis ranged from 1 day to 12 months, with a median age of 4 months. The primary sites were adrenal in 34 cases, retroperitoneum in two, mediastinum in one, and unknown in eight; the liver was involved in 24 of 31 cases, the bone marrow in 11 of 27, and the skin in 4 of 29. According to the histopathological evaluation (Shimada classification), 43 IVS-NB tumors had a favorable histology, and 2 cases showed an unfavorable histology. Three patients died of progressive disease and six of indirect tumor death. Among these three deceased cases with tumor progression, two cases showed unfavorable histology, and one case had amplified N-myc (20 copies). These data suggest that most IVS-NB can be described as a tumor presenting characteristic dissemination pattern in the younger age group, having a favorable histology and showing an excellent outcome of the patients. However, poor prognosis group in stage IVS does exist, and this group could be detected histopathologically and biologically.

Screening for neuroblastoma in North America. Preliminary results of a pathology review from the Quebec Project.

BACKGROUND: The Quebec Neuroblastoma Screening Project was initiated to assess clinical and biologic aspects of neuroblastomas detected by screening infants born in the province of Quebec from May 1, 1989, to April 30, 1994. METHODS: Infants were screened for preclinical detection of neuroblastoma by determination of catecholamine metabolites, vanillylmandelic acid (VMA), and homovanillic acid (HVA). Patients with tumors discovered through this screening as well as patients in the same birth cohort with clinically detected tumors were referred to Quebec Oncology Centers for further investigation, diagnosis, and treatment. Pathology specimens were submitted to Childrens Hospital Los Angeles for central review. Tumors were histopathologically classified according to the Shimada system. RESULTS: As of August, 1993, 340,000 infants were screened at 3 weeks and 245,000 of them were retested at 6 months of age. Thirty-one tumors were detected through this screening and removed. Histologic material was available for 27 cases: 14 were detected at 3 weeks of age and 13 at 6 months of age. Twenty-six patients had tumors with favorable histology (FH), and one patient had a Stage I tumor with unfavorable histology (UH). At the time of this writing, all mass screening patients are alive, including one child with relapsed disease. During this period, 48 tumors were detected clinically in the same birth cohort, 40 of which were evaluated histologically. Of these 40 cases, 28 of 29 tumors diagnosed in patients up to age 12 months indicated an FH, whereas 9 of 11 tumors diagnosed in patients older than age 12 months indicated a UH. All patients with FH tumors are alive including a child with relapsed disease. The single patient with UH diagnosed before age 12 months died of disease. Of the nine patients with UH diagnosed after age 12 months, four died of disease, one relapsed, and four are alive (including one treated with bone marrow transplantation) after variable follow-up periods. CONCLUSIONS: The tumors detected by mass screening, similar to those tumors detected through clinical examination before age 12 months, were predominantly FH with good prognosis. However, those tumors that were missed by screening and were detected clinically after the patient was 12 months of age were predominantly UH, with serious clinical problems. This subgroup of patients not detectable by the current screening system presents an immediate and important clinical challenge that should be addressed in future studies.

Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis.

BACKGROUND: Neuroblastomas show different histopathologic phenotypes, and the tumor cells can carry normal or multiple copies of the N-myc proto-oncogene (MYCN). Studies of the N-myc gene and histopathology of untreated primary neuroblastomas have demonstrated that both these factors are important in risk assessment. PURPOSE: Our purpose was to determine if there are any associations between N-myc gene copy number, histopathologic features, clinical stage, and progression-free survival (PFS) and if joint analyses of histopathology and N-myc gene copy number improve risk assessment. METHODS: The histopathologic phenotype and N-myc gene copy number were determined for 232 biopsy/surgery specimens obtained from untreated primary neuroblastoma patients. Tumors were classified as having favorable or unfavorable histology on the basis of Schwannian stroma (rich versus poor), neuroblastic differentiation (differentiating versus undifferentiated), and mitosis-karyorrhexis (fragmenting nucleus) index (MKI; high, intermediate, or low) in the context of age at diagnosis (Shimada classification). N-myc gene amplification was considered significant when the gene copy number was at least 10-fold higher than normal as determined by Southern blot analysis. Otherwise, tumors were classified as nonamplified for N-myc. RESULTS: Among 19 stroma-rich tumors, 11 had grossly visible neuroblastic nodules, and two of these had N-myc amplification. Of 213 stroma-poor tumors, 51 had N-myc amplification, all of which were undifferentiated, and 45 (88% of 51) had high MKI. This histologic phenotype was present in less than 10% of tumors with nonamplified N-myc. Of 162 stroma-poor tumors that showed nonamplified N-myc, 45 (28%) were differentiating and 121 (75%) had low MKI. Neuroblastomas of clinical stages I, II, and IV-S nearly always had favorable histology and no amplification of N-myc. Stage III (regional) and particularly stage IV (metastatic) tumors, however, frequently had unfavorable histologic features with or without N-myc amplification. The estimated PFS at the end of 4 years after diagnosis was 83% for patients whose tumors had favorable histology and no N-myc amplification. The estimated PFS for the patients whose neuroblastomas had unfavorable histology, however, was 29% without and 13% with N-myc amplification, respectively. Subsets of patients with stage II, III, or IV disease were identified by both histologic evaluation and N-myc analysis. Multivariate Cox regression analysis indicated that both the histologic and N-myc-based stratifications provided prognostic information that was independent of staging. CONCLUSIONS: Neuroblastomas with N-myc amplification have a characteristic histopathologic phenotype and an aggressive clinical course. In contrast, neuroblastomas without N-myc amplification exhibit a wide range of histologic features that can define prognostic subsets.

One hundred neuroblastomas detected through a mass screening system in Japan.

BACKGROUND: In Japan, a nationwide mass screening (MS) program for preclinical detection of neuroblastoma in infants was done by measuring urinary vanillylmandelic acid and homovanillic acid at the age of 6 months. In this study, clinical, histopathologic, and biologic features of 100 neuroblastomas detected through the Japanese MS are presented. METHODS: Clinical data of the MS cases were collected and histologic and biologic studies performed on the surgically resected neuroblastomas. Histopathologic evaluation was done including the Shimada classification (all tumors), N-myc oncogene status (58 tumors), and ploidy analysis (31 tumors). The serum ferritin level was measured before surgical intervention in 27 cases. RESULTS: The primary tumor sites of these cases were adrenal (69), retroperitoneum (21), and mediastinum (10). The tumors were clinical Stage I (31), II (31), III (19), IV (8), and IV-S (9); two children had bilateral primary adrenal tumors. Ninety-three percent (93/100) had favorable histology; 100% (58/58) had nonamplified N-myc oncogene expression; 81% (25/31) showed a favorable ploidy pattern, and 96% (26/27) had normal serum ferritin levels. To date, all children in this series are alive and well, although a total of 13 tumors were associated with one or two poor risk factors; 6 had unfavorable histology (UH), 5 had an unfavorable ploidy (UP) pattern, one had UH and UP, and one had an elevated ferritin level. CONCLUSIONS: The majority of neuroblastomas detected through the MS showed favorable biologic factors (biologically favorable group). However, there was a small group with histopathologic and/or biologic unfavorable factors. Patients with unfavorable factors apparently benefit most from early surgical intervention.

Neuroblastoma with a distinct organoid pattern: a clinicopathologic, immunohistochemical, and ultrastructural study.

We studied the organoid pattern in neuroblastoma, defined here as a characteristic histologic feature of the thin fibrovascular meshwork regularly surrounding the individual nests of neuroblastic cells. Among 75 neuroblastomas in our files, 11 cases were qualified as having the recognizable organoid pattern by hematoxylin-eosin stain morphology. The patients comprised five girls and six boys with ages at diagnosis ranging from 1 to 60 months (mean age, 14 months). Nine of the tumors were adrenal and two were retroperitoneal primary. The stages were I (four cases), III (two cases), IV (two cases), and IVS (two cases). All eight patients younger than 1 year are alive and well, whereas two of three patients older than 1 year died of disease. Immunohistochemical staining of those tumors having an organoid pattern showed a considerable number of S-100 protein-positive spindle cells present, mainly in the meshwork areas. Putative Schwann cells were identified ultrastructurally in five of the six tumors examined. In conclusion, organoid pattern in neuroblastoma is easily recognizable, is an indicator of good prognosis in younger children, and may well represent a close relationship between neuroblasts and putative Schwann cells.