Clear cell sarcoma of the pediatric kidney: detailed description and analysis of variant histologic patterns of a tumor with many faces.

Clear cell sarcoma of the kidney is the most frequently misdiagnosed renal tumor in children. The majority of tumors present the classic histologic pattern, which allows a definitive diagnosis. However, there are unusual cases with lack of "clear" appearance of tumor cells, predominance or exclusive presence of variant histologic patterns, and presence of "neoplastic" appearing entrapped tubules. Furthermore, a small biopsy specimen may not show the classic histologic pattern. These tumors present a diagnostic challenge for the practicing pathologist who should be aware of the deviations from the classic histologic features in order to make a correct diagnosis.

Adsorption Behavior of N(2), Water, C(6) Hydrocarbons, and Bulkier Benzene Derivative (TMB) on Na-X Zeolite and Its K(+)-, Rb(+)-, and Cs(+)-Exchanged Analogues.

The hydrothermal crystallization of X-type zeolite with a Si/Al ratio of 1.15 was achieved from the Na(2)O-Al(2)O(3)-SiO(2)-H(2)O system at 368 K under static conditions. The post-synthesis modification was carried out by a conventional ion-exchange technique to obtain K(+)-, Rb(+)-, and Cs(+)-exchanged samples with different degrees of exchange. All the samples were characterized using chemical analysis, IR, SEM, powder XRD, low-temperature nitrogen adsorption, and equilibrium sorption uptakes of different probe molecules. The relative intensities of the XRD peaks of cation-exchanged zeolite were found to be affected to different extents, depending on the nature and the concentration of nonframework cationic size, without any shift in the positions of reflection. The sorptive properties of the K-, Rb-, and Cs-exchanged samples were studied using nitrogen, water, and different C(6) hydrocarbons including bulkier benzene derivative 1,3,5-trimethylbenzene (TMB) as probe molecules. The trend observed in chemical potential estimated as a function of nitrogen coverage indicates different sorption selectivity because of differences in the cationic size and population. Sorption uptake kinetics for probe molecules such as water, n-hexane, cyclohexane, benzene, and TMB were also studied. The samples with higher degrees of exchange and/or cationic size have shown a decrease in hydrophilic character due to the formation of irregular networks of water molecules connected with preadsorbed water molecules, framework oxygen ions, and nonframework cations. Among C(6) hydrocarbons including TMB, the benzene molecule is found to be the most promising probe for the estimation of openness of structure and surface heterogeneity as well. Copyright 2001 Academic Press.

Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group Study.

PURPOSE: To prospectively analyze the outcome of patients with Stage A neuroblastoma (NB) treated with surgery alone, especially with regard to the prognostic significance of age, tumor site, MYCN copy number, tumor cell ploidy, and histology. PATIENTS AND METHODS: The clinical course of 329 patients with Stage A disease registered on the POG NB Biology Study #9047 between February, 1990 and October, 1997 were evaluated. Age, tumor site, MYCN copy number, tumor cell ploidy, and histology were analyzed for their impact on event-free survival (EFS) and survival (S). RESULTS: The 5-year estimated EFS and S rates for the 329 patients were 91% (+/-3%) and 96% (+/-2%), respectively. The EFS rate was similar for infants younger than 12 months and children age 12 months or older, but age older than 12 months was predictive of lower S rates (P = 0.044). Patients with adrenal, abdominal non-adrenal, thoracic, and cervical tumors had similar S rates. The majority of patients had tumors with favorable biologic features, and only 3% had MYCN amplification. For infants with diploid tumors, the EFS rate was 82% (+/-16%), but effective therapy yielded an S rate of 100%. Rate of S was 80% (+/-26%) and 64% (+/-27%) for patients with unfavorable tumor histology and MYCN-amplified tumors, respectively. CONCLUSION: The outcome for patients with Stage A NB treated with surgery alone is excellent. Although EFS and S rates were significantly worse for patients with MYCN-amplified tumors, a subset achieved long-term remission after surgery alone. For patients with Stage A and MYCN amplification, additional factors are needed to distinguish the patients who will achieve long-term remission with surgery alone from those who will develop recurrent disease.

Castleman's disease of the left triceps in a child suspected to be a small round cell tumor of childhood.

Castleman's disease (CD) is histologically characterized by a proliferation of polyclonal small lymphocytes and plasma cells. The clinical presentation varies widely, but most commonly manifests as a solitary mediastinal mass, incidentally found on radiographic examination. We present a case of a 10-year-old girl who exhibited a left arm mass which, preoperatively and on frozen section, was diagnosed as a small round cell tumor of childhood (SRCT). This report emphasizes the unusual location of CD in the soft tissue and as a rare entity to be considered in the differential diagnosis of SRCT.

Molecular and virologic characteristics of lymphoid malignancies in children with AIDS.

PURPOSE: To characterize AIDS-associated lymphoid malignancies in children. PATIENTS AND METHODS: We studied lymphomas and B-cell leukemias from 25 children with AIDS for immunoglobulin heavy chain gene clonality, c-myc oncogene abnormalities, and presence of HIV and Epstein-Barr virus. RESULTS: Monoclonal immunoglobulin gene rearrangements were identified in 22 of 23 cases tested, the single exception being one of mucosa-associated lymphoid tissue. Immunoglobulin gene/c-myc translocations were found in 3 of 4 cases of B (surface immunoglobulin-positive)-acute lymphoblastic leukemia, 8 of 11 small noncleaved cell lymphomas, and 1 of 5 large cell lymphomas. Mutations of c-myc were found in 2 of 13 small noncleaved cell lymphomas, 1 of 2 Epstein-Barr virus-positive mucosa-associated lymphoid tissue neoplasms, and 1 of 4 Epstein-Barr virus-negative B-acute lymphoblastic leukemia. Six small noncleaved cell lymphomas, both mucosa-associated lymphoid tissue neoplasms and one of large cell lymphoma had high levels of Epstein-Barr virus in tumor tissue. Hodgkin's disease tissue and B-acute lymphoblastic leukemia tumors were negative for EBV. Proviral HIV-1 was not detected in any tumor. CONCLUSIONS: AIDS-associated lymphoid malignancies in children appear to have a different distribution of histologic subtypes than adult HIV-infected individuals, fewer large cell lymphomas occur in children. The small noncleaved cell lymphomas exhibit a lower frequency as well as different locations of c-myc mutations than AIDS-associated small noncleaved cell lymphomas in adults.

Primary PNET of kidney: report of two cases and review of literature.

PNET of the kidney is a rare tumor with only a few published reports. In view of poorer prognosis and different therapeutic approach, renal PNET should therefore be differentiated from other primary renal neoplasma such as Wilms tumor, renal neuroblastoma and malignant rhabdoid tumor which on histology resemble renal PNET. Two cases of renal PNET have been described in this report. Cut surface of the tumor in both cases was greyish white lobulated, with multiple tiny cystic areas. Histologically, tumor consisted of loosely cohesive sheets of small to medium sized monomorphic cells with round nuclei and little cytoplasm. Tumor cells showed diffuse strong membrane positivity for MIC2 and focal weak to moderate positivity for NSE and vimentin. Renal PNET should therefore be included in differential diagnosis of rapidly enlarging renal lumps presenting with local infiltration and aggressive behaviour, particularly in children and young adults. Diffuse strong membrane positivity for MIC2 in PNET is helpful in differentiating it from other primary renal neoplasms.

Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee.

BACKGROUND: As part of the international cooperative effort to develop a complete set of International Neuroblastoma Risk Groups, the International Neuroblastoma Pathology Committee (INPC) initiated activities in 1994 to devise a morphologic classification of neuroblastic tumors (NTs; neuroblastoma, ganglioneuroblastoma, and ganglioneuroma). METHODS: Six member pathologists (H.S., I.M.A., L.P.D., J.H., V.V.J., and B.R.) discussed and defined morphologically based classifications (Shimada classification; risk group and modified risk group proposed by Joshi et al.) on the basis of a review of 227 cases, using various pathologic characteristics of the NTs. The classification-grading system was evaluated for prognostic significance and biologic relevance. RESULTS: The INPC has adopted a prognostic system modeled on one proposed by Shimada et al. It is an age-linked classification dependent on the differentiation grade of the neuroblasts, their cellular turnover index, and the presence or absence of Schwannian stromal development. Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and 4) ganglioneuroblastoma, nodular (composite Schwannian stroma-richlstroma-dominant and stroma-poor). Specific features, such as the mitosis-karyorrhexis index, the mitotic rate, and calcification, were also included to allow the prognostic significance of the classification to be tested. Recommendations are made regarding the surgical materials to use for an optimal pathobiologic assessment and the practical handling of samples. CONCLUSIONS: The current article covers the essentials and important points regarding the histopathologic evaluation of NTs. Using the morphologic criteria described herein, the INPC is proposing the International Neuroblastoma Pathology Classification. It is reported in a companion article in this issue (Cancer 1999;86:363-71).

The International Neuroblastoma Pathology Classification (the Shimada system).

BACKGROUND: The International Neuroblastoma Pathology Committee, which is comprised of six member pathologists, was convened with the objective of proposing a prognostically significant and biologically relevant classification based on morphologic features of neuroblastic tumors (NTs) (i.e., neuroblastoma, ganglioneuroblastoma, and ganglioneuroma). METHODS: A total of 227 cases were reviewed. Consensus diagnoses from morphologic features (criteria described separately) based on five of six or six of six agreements by the reviewer pathologists were used for prognostic analysis. Prognostic effects of morphology, both individual and in combination, taken in conjunction with age (Shimada classification, histologic grade, and risk group), were analyzed. RESULTS: Approximately 99% of cases (224 of 227) had consensus diagnoses for categorization: neuroblastoma (Schwannian stroma-poor), 190 cases; ganglioneuroblastoma, intermixed (Schwannian stroma-rich), 5 cases; ganglioneuroma (Schwannian stroma-dominant) maturing, 1 case; ganglioneuroblastoma, nodular (composite Schwannian stroma-rich/stroma-dominant and stroma-poor), 19 cases; and NT-unclassifiable, 9 cases. For the NTs, subtype (93% consensus: undifferentiated, 6 cases; poorly differentiated, 155 cases; and differentiated, 15 cases), mitosis-karyorrhexis index (90% consensus: low, 94 cases; intermediate, 40 cases; and high, 37 cases), mitotic rate (75% consensus: low, 89 cases; high, 50 cases; and not determined, 4 cases), and calcification (100% consensus: yes, 110 cases and no, 80 cases) were recorded. Statistical analysis demonstrated that the Shimada classification system (90% consensus; 3-year event free survival: 85% for the group with favorable histology and 41% for the group with unfavorable histology; P = 0.31 x 10(-9)) had a significantly stronger prognostic effect than individual features and other combinations. CONCLUSIONS: The International Neuroblastoma Pathology Classification, a system based on a framework of the Shimada classification with minor modifications, is proposed for international use in assessing NTs.

Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience--a pediatric oncology group study.

PURPOSE: Although a high rate of spontaneous regression is observed in infants with stage D(S) neuroblastoma (NB), survival is not uniform. To determine the prognostic relevance of age at diagnosis, therapy, and tumor biology in infants with stage D(S) NB, we reviewed the Pediatric Oncology Group (POG) experience. PATIENTS AND METHODS: A review of patients diagnosed with stage D(S) NB registered on POG protocols was performed. Survival according to age at diagnosis, treatment, and tumor biology was determined. RESULTS: Between 1987 and 1996, 110 infants with stage D(S) NB had an estimated 3-year survival rate of 85% +/- 4%; survival rate was 71% +/- 8% for infants 2 months of age or younger, and 68% +/- 12%, 44% +/- 33%, and 33% +/- 19% for patients with diploid, MYCN-amplified, and unfavorable histology tumors, respectively. Survival rates were similar for patients who received adjuvant chemotherapy versus those who did not (82% +/- 5% v 93% +/- 6%, respectively; P = .187). Furthermore, there was no statistical difference in survival rate for patients who underwent complete resection of their primary tumor compared with those who underwent partial resection or biopsy only (90% +/- 5% v 78% +/- 7%, respectively; P = .083). CONCLUSION: Our review confirmed that the survival of infants with stage D(S) NB is excellent. However, subsets of patients with poor prognosis can be identified by young age and unfavorable biologic factors. More effective therapy is needed for the group of stage D(S) infants who show unfavorable clinical and biologic features.

The risk of nephrectomy during local control in abdominal neuroblastoma.

METHODS: Eight hundred sixty-eight children presenting from 1981 to 1991 were treated on five multiagent chemotherapy protocols by members of the Pediatric Oncology Group for advanced-stage neuroblastoma with large primary tumors crossing the midline or distant metastasis. Of these children, 696 had abdominal (adrenal or paravertebral) primary tumors. One hundred sixteen children underwent greater than 50% surgical resection of these abdominal primary tumors before chemotherapy, and 233 underwent similar surgery after induction chemotherapy. RESULTS: Among the 349 who underwent surgical resection, 52 children (14.9%) had nephrectomy or renal infarction during surgery for local control. There was a 25% incidence among those with initial resection (29 patients) and a 9.9% incidence in the postchemotherapy resections (23 patients). Reasons for nephrectomy given by the surgeons included direct involvement of the kidney by adjacent tumor (17 children), clinical impression that the tumor was a Wilms' tumor (11 children), renal vessels could not be separated from the tumor (10 children), extensive tumor surrounding the kidney (8 children), postoperative renal infarction (4 children), marked decrease in unilateral renal function after chemotherapy (1 child), and position of the tumor posterior to the kidney and vena cava making resection without nephrectomy impossible (1 child). Of the patients undergoing nephrectomy, four children had an upper pole nephrectomy in conjunction with their adrenalectomy and resection of the tumor. Pathological review of the resected tumor available in 47 cases demonstrated direct involvement of the renal parenchyma in 18 cases (38% of the nephrectomies) and in 5.2% of those undergoing resection. In children undergoing initial resection, the risk for nephrectomy (as calculated by the methods described by Gart) was more than twice compared with those undergoing resection after chemotherapy (P = .012; odds ratio, 2.32; 95% confidence interval of 1.23 to 4.42). CONCLUSIONS: This review confirms that renal parenchymal involvement does occur in a significant number of children with abdominal neuroblastoma. It also suggests that preoperative chemotherapy may decrease the number of nephrectomies required to achieve a total or subtotal resection.

Benign and malignant smooth muscle tumors containing Epstein-Barr virus in children with AIDS.

Smooth muscle tumors (leiomyosarcomas) are the second most prevalent malignancy of children with the acquired immunodeficiency syndrome (AIDS). We have investigated the tumors, plasma, and peripheral white blood cells of eight children with AIDS with smooth muscle tumors for evidence of tumor association with human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV). Very low levels of HIV were found in the tumors of the AIDS patients, probably resulting from blood-borne carriage of virus. These smooth muscle tumors had very high quantities of EBV in all the tumor cells by in situ hybridization, with an average of 4.5 EBV genomes per cell by quantitative polymerase chain reaction amplification. Increased amounts of EBV were found in the peripheral blood cells of two AIDS patients before the time of tumor diagnosis. EBV clonality studies demonstrated different monoclonal EBV infection of two separate colonic tumors from one patient, and dual or mixed monoclonal EBV infection in another patient. The muscle cells of leiomyomas and leiomyosarcomas of patients with AIDS demonstrated prominent staining with antibodies to the EBV receptor. The uniform distribution and striking amount of EBV in the tumor cells demonstrates that EBV is capable of infecting smooth muscle cells and that these cells support EBV replication. Clonal EBV proliferation suggests that EBV infection occurs at an early stage of tumor development. These findings indicate that EBV has a causal role in the oncogenesis of leiomyosarcomas of patients with AIDS.

Correlation between morphologic and nonmorphologic prognostic markers of neuroblastoma.

Morphologic (Shimada classification--SC, original and modified histologic grades--OHG and MHG) and nonmorphologic (serum LDH, 1 p del, DNA index, N-myc copy number, telomerase activity, and expression of MRP, MDR1, and TRK) prognostic markers for NB have been reviewed. The functional role of these nonmorphologic markers in the development and progression of this disease include abnormal cell proliferation, resistance to chemotherapeutic agents, and induction of apoptosis. A statistically significant association between high OHG/MHG (grade 3), DNA index of 1 (diploidy), > 1 copy of N-myc per haploid genome and serum LDH of > or = 1500 IU/1 (p < 0.001 for each) has been described. In SC, undifferentiated histology and high MKI are associated with N-myc amplification. However, a lack of correlation between morphology and N-myc amplification has been found in localized NB. Confirmation of these observations must now be obtained on larger numbers of prospectively studied cases. Data on correlation for various prognostic markers could provide guidelines for identification of subsets of NB having strongly significant, readily determinable, reproducible, and relatively inexpensive prognostic markers that could ultimately be used to design an algorithm for risk-specific therapy.

Crohn's disease of the prepuce in a 12-year-old boy: a case report and review of the literature.

We report a case of Crohn's disease with involvement of the foreskin in a 12-year-old boy. One year previously, on the basis of clinical features (diarrhea with blood, perianal fissures) and histologic examination, a diagnosis of Crohn's disease was made. Subsequently, he developed phimosis and balanitis and underwent circumcision. Sections submitted from the foreskin revealed noncaseating granulomatous inflammation consistent with Crohn's disease. Crohn's disease with involvement of the genitalia is unusual. Only 26 cases including our case have been reported in the scientific literature. We have analyzed these cases with emphasis on gender, age, clinical features, duration of Crohn's disease, and probable mode of spread to the genitalia. Careful examination of sections from genital lesions, including those submitted from the foreskin, is essential to detect small isolated granulomas that may then lead to the diagnosis of inflammatory bowel disease.

The spectrum of mucosa-associated lymphoid tissue lesions in pediatric patients infected with HIV: A clinicopathologic study of six cases.

Mucosa-associated lymphoid tissue (MALT) lesions in nonimmunocompromised individuals include reactive lymphoid proliferations and both low- and high-grade lymphoid neoplasms. These lesions occur at extranodal mucosal sites, such as the gastrointestinal tract, bronchus, salivary gland, and other locations. The spectrum of MALT lesions in children with HIV infection had not been previously described. In this study, six cases that demonstrated the spectrum of MALT lesions in pediatric patients, aged 28 months to 23 years, who had HIV infection were described. Half the patients acquired the infection perinatally, and half acquired it by transfusion. Mucosal sites of involvement included the salivary gland (4 patients), bronchiolar mucosa (2 patients), and oropharyngeal mucosa (1 patient). One patient had lesions in lung and oropharynx sequentially; all others had involvement of solitary sites. The histologic diagnoses included myoepithelial sialadenitis (MESA), MESA with low-grade MALT lymphoma, typical low-grade MALT lymphoma, diffuse large cell lymphoma (DLCL), and atypical pulmonary lymphoid hyperplasia and lymphoid interstitial pneumonitis complex. The two cases of high-grade DLCL were confined to mucosal sites (tonsil and parotid); in one of these patients, a previous biopsy specimen showed a MALT lesion with low-grade features. In two cases, quantitation of the Epstein-Barr virus (EBV) genome by the polymerase chain reaction showed a very high copy number in peripheral blood mononuclear cells but a low copy number in the MALT lesion, which suggested that MALT lesions may not be directly associated with EBV infection. Two patients who had high-grade tumors (DLCL) were successfully treated with chemotherapy and radiation therapy. The remaining patients, all of whom had low-grade MALT lesions, received either corticosteroids or alpha-interferon or no specific therapy; in all patients, the lesions followed an indolent clinical course. Clinicians and pathologists should be alert to the possibility that MALT lesions, including MALT lymphomas, may be present in children who have AIDS.

Chemotherapy for patients with recurrent or refractory neuroblastoma: a POG Phase II study.

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of three different salvage regimens (Rx) in children with recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Forty-six children with recurrent or refractory neuroblastoma received treatment according to one of three regimens: Rx 1 (five patients), high-dose cisplatin (HDP) (200 mg/m2) with concurrent sodium thiosulfate (STS) (9.9 g/m2) as a nephroprotectant and etoposide (VP-16) (200 mg/m2/day for 3 days); Rx 2 (22 patients), high-dose carboplatin (HD-CBDCA) (500 mg/m2/day for 2 days) and VP-16 (100 mg/m2/day for 3 days); Rx 3 (19 patients), ifosfamide (1.5 g/m2/day for 3 days) followed by CBDCA (400 mg/m2) on day 4. Chemotherapy was administered every 3-4 weeks. Responses were assessed following four courses with or without surgery. Patients achieving less than a partial response (PR) on their primary treatment were crossed over to the next regimen (i.e., Rx 1 --> Rx 2 <--> Rx 3). RESULTS: Rx 1 was ended early owing to grade 4 nephrotoxicity in two patients following their first course. Ten of 22 evaluated patients (45%) primarily (n = 19) or secondarily (n = 3) treated by Rx 2 responded [five complete response (CR) and five PRs]. Nine of the 23 evaluated patients (39%) on Rx 3 as primary (n = 18) or secondary (n = 5) treatment responded (one CR and eight PRs). Grades 3-4 neutropenia and thrombocytopenia occurred after 80% and 50% of courses administered on Rx 2 and Rx 3, respectively. Central venous line infections were the most commonly documented infections on these regimens. CONCLUSIONS: Rx 2 and Rx 3 are active combinations in patients with recurrent or refractory neuroblastoma and are associated with manageable toxicity. HDP administered as a short i.v. infusion with concurrent STS infusion cannot be safely given to children with neuroblastoma pretreated with cisplatin.

Pathology of acquired immunodeficiency syndrome (AIDS) in children.

OVERVIEW: Acquired Immunodeficiency Syndrome (AIDS) was first described to occur in children in 1983. With experience of increasing number of cases of AIDS, pathologic lesions in various organs and tissues such as lungs, brain, G.I. tract, heart, blood vessels, lymph nodes, spleen, bone marrow, etc. became evident in autopsy and biopsy specimens. These pathologic lesions were classified into four groups based on known or suspected pathogenesis: 1) Primary lesions due to Human Immunodeficiency (HIV) infection itself (lymph nodes, brain, etc) 2) associated lesions related to direct or indirect sequelae of HIV infection (Opportunistic infections, PLH/LIP complex, etc) 3) lesions of undetermined pathogenesis, (cardiomyopathy, arteriopathy, thrombocytopenia, nephropathy, etc) 4) lesions of multifactorial pathogenesis (villous atrophy of intestine, thymic lesions, etc). UPDATE: In recent years the emphasis of pathologic study is on the reactive and neoplastic proliferative disorders. These disorders include nodal and extranodal lymphoproliferative lesions (such as myoepithelial sialadenitis, malignant lymphomas, etc), smooth muscle tumors (SMTs), Kaposi's sarcoma, Human Papilloma virus associated genital lesions and miscellaneous tumors. In a recent study, it has been shown that Epstein-Barr virus (EBV) may be related to the pathogenesis of SMTs. The most recently recognized lymphoproliferative lesions include those of mucosa associated lymphoid tissue (MALT) of salivary glands, lungs and tonsils. The MALT lymphomas in children with AIDS are responsive to therapy and tend to take an indolent clinical course. Therefore recognition of MALT lymphomas as a distinctive lesion in pediatric AIDS is of practical importance. In this view of increasing incidence of HIV and HPV infections in adolescent females seen in certain countries attention should also be focused on early detection of HPV related genital lesions so that their possible progression to intraepithelial and invasive cervical carcinoma can be prevented.