Conventional versus modified morphologic criteria for ganglioneuroblastoma. A review of cases from the Pediatric Oncology Group.

BACKGROUND: Conventional criteria for ganglioneuroblastoma (GNB) do not require the presence of ganglioneuromatous component for pathologic diagnosis. This leads to inclusion of a mixed variety of neuroblastic tumors in the category of GNB. Therefore, GNB diagnosed by conventional criteria includes tumors showing more than 5% ganglion cells but no predominant ganglioneuromatous component, as well as tumors containing predominant ganglioneuromatous component. By previously described modified criteria, the former would be considered differentiating neuroblastoma (NB), and only the latter would be considered GNB. Data on Pediatric Oncology Group cases were analyzed to compare the prognostic subgroups of GNB diagnosed by conventional and modified criteria. The two prognostic subgroups (low risk and high risk) were defined on the basis of previously described prognostic differences between histologic grades of differentiating NBs and subtypes of GNB. METHODS: Pathologic data from cases of neuroblastic tumors registered on Pediatric Oncology Group NB protocols 8104 and 8441 were reviewed. The GNBs diagnosed by conventional and modified criteria were divided into low-risk and high-risk histology subgroups as follows: (1) GNB by conventional criteria: low-risk group, differentiating NB of histologic grades 1 and 2 and GNB of intermixed and borderline subtypes; high-risk group, differentiating NB of histologic grade 3 and GNB of nodular subtype; (2) GNB by modified criteria: low-risk group, GNB of intermixed and borderline subtypes; high-risk group, GNB of nodular subtype. RESULTS: The low- and high-risk subgroups of GNBs diagnosed by conventional (69 cases) and modified (36 cases) criteria showed statistically significant differences in survival (P = .03 and .01, respectively). However, from the histologic point of view, GNBs diagnosed by modified criteria form a more uniform morphologic group, which can be divided into low- and high-risk subgroups by a single set of morphologic criteria. In contrast, GNBs diagnosed by conventional criteria form a heterogeneous group, which requires two sets of criteria (ie, histologic grade and subtypes of GNB) for its classification into low- and high-risk subgroups. CONCLUSIONS: The modified criteria for GNB define a morphologically uniform group of neuroblastic tumors to which a single set of prognostic criteria can be applied. It is recommended that the term GNB should be used both clinically and pathologically to designate a distinctive subgroup of neuroblastic tumors, in contrast to the current use, which designates both NB and GNB.

Correlation between morphologic and other prognostic markers of neuroblastoma. A study of histologic grade, DNA index, N-myc gene copy number, and lactic dehydrogenase in patients in the Pediatric Oncology Group.

BACKGROUND: Histologic grades (HG), N-myc (NM) gene copy number, DNA index (DI), and serum lactic dehydrogenase (LDH) have been shown to be related to prognosis in neuroblastoma. The relationship between HG and nonmorphologic prognostic markers has not been investigated previously. METHODS: Each prognostic marker was determined independently and without the knowledge of clinical features and outcome by different investigators in 275 (HG), 96 of 275 (DI), 94 of 275 (NM), and 224 of 275 patients (LDH) with neuroblastoma by methods described previously. Patients younger than 2 years of age were included in the analysis for DI. Patients of all ages were included in the analysis of HG, NM, and LDH. RESULTS: A statistically significant association of low HG (1 and 2) was found with DI of more than 1 (hyperdiploid), single copy of NM gene per haploid genome, and an LDH of less than 1500 IU/l (P value for each, < 0.001), factors that are associated with better prognosis. High HG was associated with DI of 1 (diploidy), amplified NM gene, and an LDH of 1500 or more, factors that are associated with aggressive behavior. CONCLUSION: The value of HG is strengthened by its statistically significant association with features that reflect tumor cell biology of neuroblastoma. In view of the tissue sample size required for determination of HG, consideration should be given to obtaining such a sample in as many patients as is feasible if there is no contraindication to surgery. Nonmorphologic prognostic markers, when used in concert with HG, would provide a basis for individualized risk-specific therapy of this disease.

Systematization of primary histopathologic and fine-needle aspiration cytologic features and description of unusual histopathologic features of neuroblastic tumors: a report from the Pediatric Oncology Group.

On the basis of a detailed review of the primary histopathologic features of 239 cases and the fine-needle aspiration cytologic features of seven cases, a systematized schema of differentiation, progressive maturation and organization, and biologic behavior in neuroblastic tumors (NTs) is presented. The differentiation is of the gangliocytic and schwannian lineages. Maturation occurs in differentiating neuroblasts, leading to the formation of various stages of ganglion cells and Schwann cells. Organization is characterized by nesting pattern, rosette formation, parallel arrangement of neuropil, and alignment of Schwann cells along the neurites. According to this schema the NTs can be arranged in the following order: undifferentiated, poorly differentiated, and differentiating neuroblastoma; nodular, intermixed, and borderline ganglioneuroblastoma; and ganglioneuroma. Formulation of such a schema is helpful in gaining a better understanding of the complex pathologic features and in defining the criteria for various types of NTs. Therefore, the schema also would be helpful in achieving uniformity and reproducibility of the diagnosis of various types of NTs. Previously unreported features related to shape, size, nucleus, and cytoplasm of neuroblasts; secondary changes and patterns; changes in the fibrovascular septa; and other morphologic aspects of NTs and features (such as large tumor cells, karyorrhectic cells in fine-needle aspiration biopsy, tumor giant cells, anaplasia, and nesting pattern of tumor cells that have not been sufficiently emphasized) also are described. The importance of these previously unreported and insufficiently emphasized features relates to the histologic and cytologic diagnosis of NTs. For example, some of the features, such as starry sky appearance and spindle-shaped neuroblasts, may be misleading if seen in a small biopsy specimen. Others, such as tumor giant cells resembling ganglion cells and nesting pattern, will provide clues to the correct diagnosis. Some of the features, such as sclerosing pattern, hyalinization, and dense lymphoplasmacytic infiltration, may be related to the phenomenon of regression exhibited by neuroblastomas.

Age-linked prognostic categorization based on a new histologic grading system of neuroblastomas. A clinicopathologic study of 211 cases from the Pediatric Oncology Group.

Histologic sections (minimum of four sections per patient) from 211 patients with neuroblastoma were reviewed. The tumors were resected before therapy, which was standardized according to age and stage. Low mitotic rate (MR) (less than or equal to ten per ten high-power fields) and calcification emerged as the most significant prognostic features after statistical analysis by stepwise log-rank tests (P less than 0.0001 and P = 0.0065, respectively). Histologic Grades 1, 2, and 3 were defined on the basis of the presence of both, any one, or none of these two prognostic features, respectively (Grade 3 had absence of low MR, i.e., these tumors had high MR [greater than ten per ten high-power fields]). Statistically significant differences in survival were observed in the grades after adjusting for age and stage (P less than 0.001). The degree of differentiation, although significant by itself, was no longer significant after adjusting for the grades. Age groups (less than or equal to 1 versus greater than 1 year of age), which also emerged as an independent prognostic feature (P less than 0.001), were linked with the grades to define two risk groups as follows: (1) a low-risk (LR) group consisting of patients in both age groups with Grade 1 tumors and patients 1 year of age or younger with Grade 2 tumors and (2) a high-risk (HR) group consisting of patients older than 1 year of age with Grade 2 tumors and patients in both age groups with Grade 3 tumors. The difference in survival between LR (160 cases) and HR groups (51 cases) was statistically significant (P less than 0.001). Concordance between these LR and HR groups and the Shimada classification was observed in 84% of cases. The new histologic grading system has the following advantages: (1) use of familiar terminology and histologic features in the grading system and (2) relative ease of assessment because the degree of differentiation does not need to be determined. The grading system should be tested on a new data set with an appropriate histologic sample of similar size to confirm these results.

Recommendations for modification of terminology of neuroblastic tumors and prognostic significance of Shimada classification. A clinicopathologic study of 213 cases from the Pediatric Oncology Group.

To develop consistency in terminology and pathologic criteria, the authors reviewed the literature and 213 cases of neuroblastic tumors (NT) registered with Pediatric Oncology Group (POG) protocols 8104 and 8441. The patients were given standardized therapy stratified according to POG stage and patient age, and four or more histologic sections of primary tumor resected before therapy were available in each of these 213 cases. All stages were represented. The recommended nomenclature combines conventional terms and criteria with those used by Bove and McAdams and Shimada et al. The main features of the recommended nomenclature are as follows: (1) the terms neuroblastoma (NB) and ganglioneuroblastoma (GNB) are retained instead of stroma-poor NB and stroma-rich NB, recommended by Shimada et al.; (2) undifferentiated NB is considered a subtype separate from poorly differentiated NB; and (3) the term GNB is used only when there is a predominant ganglioneuromatous component admixed with the minor neuroblastomatous component. With the use of these criteria and terms, the Shimada classification was determined in the 213 cases. The results showed that, even after stratification for age, POG stage, and primary site, there is a statistically significant difference in survival rate between favorable histologic and unfavorable histologic prognostic subgroups. The authors recommend that definitive prognostic categorization of an NT according to Shimada classification should be done only when adequate histologic material is available from a primary tumor resected before any other therapy. Categorization done on histologic material from small biopsy specimens, previously treated primary tumors, or metastatic sites should be considered tentative.

Small-intestinal brushing cytology in the diagnosis of cryptosporidiosis in AIDS.

We report the cytologic findings of small intestinal brushing material showing cryptosporidiosis in two patients with acquired immunodeficiency syndrome (AIDS). Cryptosporidia measuring approximately 2-4 mu were aligned along the surface of the glandular cells, although many freely dispersed organisms were also present. The differential diagnoses of other structures that could be confused with cryptosporidia are also presented in this article. Small-intestinal brushing cytology may complement endoscopic biopsy in the workup of diarrheal diseases in AIDS, especially in patients with thrombocytopenia, since the bleeding disorder may be a contraindication for endoscopic biopsy.

Diagnostic accuracy and role of immediate interpretation of fine needle aspiration biopsy specimens from various sites.

A statistical analysis of the accuracy of the immediate interpretation of 425 fine needle aspiration (FNA) biopsies from various sites was performed. Preliminary interpretation of Diff-Quik-stained smears was rendered within a few minutes after performing the FNA biopsy, using diagnostic terminology similar to that of a surgical pathology report. The immediate assessment was documented in the formal cytology report and compared to the final diagnosis. For the entire series, the immediate interpretation had a sensitivity of 96%, a specificity of 97%, a positive predictive value (PV) of 98%, a negative PV of 95% and an efficiency of the test of 96%. There were 14 false-negative or falsely insufficient immediate interpretations and one false-positive immediate diagnosis. The diagnostic accuracy of the immediate interpretation of FNA biopsies from specific sites was also calculated; FNA biopsies of the pancreas were the least accurate procedure, having a sensitivity of 60% but a specificity of 100%. The role of the immediate interpretation of FNA biopsies is similar to the use of frozen sections in surgical pathology. An immediate assessment can (1) determine whether an adequate specimen is present, (2) render a specific preliminary diagnosis, (3) guide further clinical investigations or treatment, and (4) determine whether ancillary studies are needed to make a more accurate or specific diagnosis from the FNA specimen. Our results indicate that the immediate interpretation of FNA biopsies is an accurate procedure that should be routinely employed.

Fine-needle aspiration cytology of postirradiation sarcomas, including angiosarcoma, with immunocytochemical confirmation.

Postirradiation sarcomas are an unusual but well-recognized late effect of cancer therapy. In this article, a fine-needle aspiration (FNA) series of four cases is presented. There were three female patients and one male patient, with an age range of 28-55 yr (mean, 41). Two of the patients were irradiated for uterine cervical carcinoma while the other two received irradiation for malignant lymphoma. The time interval to the development of the postirradiation sarcoma ranged from 10 to greater than 20 yr. There were a postirradiation synovial sarcoma of the buttock region, malignant fibrous histiocytoma of the bone (femur), and rhabdomyosarcoma and angiosarcoma of the retroperitoneum. A spectrum of cytologic findings was encountered, reflecting the specific types of sarcomas. Immunocytochemical studies performed on the aspirated material from the angiosarcoma demonstrated the utility of immunoperoxidase stains for ULEX europaeus agglutinin-1 (UEA-1) and, to a lesser degree, factor VIII-related antigen antibody, confirming the vascular nature of this malignancy. The FNA findings from all four cases demonstrated cytologic features that allowed recognition of this unusual complication of irradiation treatment. This article confirms the utility of FNA cytology in following patients with previous malignancies and differentiating a postirradiation sarcoma from recurrent carcinoma.

Fine needle aspiration cytology of tuberculosis of the lumbar vertebrae (Pott's disease).

The cytomorphologic features of tuberculosis of the lumbar vertebra having a granulomatous pattern diagnosed by fine needle aspiration (FNA) biopsy are reported in a 72-year-old woman with a prior history of malignant lymphoma treated by chemotherapy. Cytologic examination revealed microtissue fragments of cohesive cells, including epithelioid histiocytes and scattered, multinucleated Langhans-type giant cells. This is believed to be the first reported case of vertebral tuberculosis (Pott's disease) diagnosed by FNA cytology and confirmed by culture of the aspirate material. This case illustrates the value of FNA cytology in the diagnosis of nonneoplastic skeletal lesions and confirms the value of FNA biopsy the early detection of infectious processes in patients with malignancy.

The role of fine-needle aspiration biopsy in the rapid diagnosis and management of thyroid neoplasm.

This report describes our 5-year experience with fine-needle aspiration (FNA) biopsy of the thyroid in a 560-bed teaching hospital. Three hundred nine FNA biopsies were performed primarily by one endocrinologist and interpreted by several pathologists. Analysis of the data reveals the sensitivity of the procedure is 93%, specificity is 95.1%, and the positive and negative predictive values are 88.9% and 96.5%, respectively. This data confirms the diagnostic accuracy of FNA biopsy. Complications were seen in 6 of 309 cases (1.9%) and were relatively mild. Nearly 75% of the cases in the series were cytologically diagnosed as nonneoplastic. Fine-needle aspiration biopsy identified 19.4% of the cases needing surgery, of which 72% had neoplastic nodules, confirming the selection role of the procedure. The management of thyroid nodules is discussed and a selective review of the FNA literature is presented. The authors believe that our experience rebuts the argument that special referral centers are needed to interpret the cytologic material. Several well trained surgical pathologists can become proficient in interpreting the FNA biopsies without significant loss in accuracy, and thereby render a definite diagnosis in the vast majority of the cases. Accordingly, the authors recommend FNA of the thyroid as the initial diagnostic test in the evaluation of thyroid nodules.

Ascitic fluid cytology in a case of metastatic malignant mixed mesodermal tumor of the ovary.

The cytologic features of the abdominal fluid from a patient with a malignant mixed mesodermal tumor (MMMT) of the ovary are presented. Both malignant epithelial and stromal elements were cytologically appreciated and confirmed by histologic examination. Other ovarian neoplasms that can present with malignant sarcomatous elements or mixed epithelial and sarcomatous elements are discussed; this case documents the importance of recognizing these features when staging patients with unusual ovarian neoplasms. To our knowledge, this is the first complete report of the ascitic fluid cytology of an MMMT of either ovarian or uterine origin.

Fine-needle aspiration versus large-needle biopsy or cutting biopsy in evaluation of thyroid nodules.

This report describes our experience with both fine-needle aspiration (FNA) biopsies and large-needle biopsies (LNB) or core biopsies (CB) performed at the same time on 23 patients out of a series of 309 patients examined by the FNA technique. There was no significant differences in diagnostic accuracy of tissue obtained with the FNA technique when compared with the LNB or CB biopsy technique. While FNA always yielded tissue adequate for diagnosis, the LNB, and/or CB technique yielded tissue insufficient for diagnosis in four of 26 biopsies (15.4%). We believe that the FNA is better able to sample a mass with fewer insufficient specimens. Using FNA, the diagnosis can be rendered more rapidly, at lower cost, and with decreased potential for complications. The adequacy of the FNA biopsies can be assessed immediately using a modified Wright stain (Diff-Quik). Repeat biopsies can be performed that better sample the lesions with increased patient acceptance.

Aspiration biopsy cytology of malignant schwannoma metastatic to the lung.

The aspiration biopsy cytologic features of a malignant schwannoma metastatic to the lung in a 39-year-old black female with von Recklinghausen's disease are reported. Cytologic features of malignant sarcomas having a spindle-cell pattern are described along with a discussion of the cytologic differential diagnosis. This is believed to be the first reported case of a malignant schwannoma involving the lung diagnosed by aspiration cytology and demonstrates the usefulness of the technique in evaluating patients with metastatic sarcomas.

Long-term incompatible kidney survival in outbred higher primates without chronic immunosuppression.

Transplantation between non-identical humans has been limited by the requirement for chronic immunosuppression (CI). This study demonstrates in a nonhuman primate model that long-term acceptance of incompatible kidney allografts can be achieved without the use of CI. Following incompatible kidney transplantation, rhesus monkey recipients were given a 5-day course of clinical rabbit antithymocyte globulin (RATG). On day 12, unfractionated donor bone marrow (BM) was infused intravenously. Recipients were monitored for T-cell levels and T-cell subset levels with monoclonal antibodies and for responses in one way MLR. Graft survival in untreated control animals was 9.2 +/- 2.8 days. In six animals given RATG only, all died of rejection at a mean 35.8 +/- 5.7 days. Of five animals given RATG and donor BM (mean 2.5 RhLA mismatches, mean MLC 12.7), four are alive at 150 days, 248 days, 342 days, and 401 days (median 248 days). The ATG-BM infused group showed a prolonged imbalance of their OKT4/OKT8 cell ratio and cellular suppression of MLR responsiveness. The long-term survival obtained in these outbred primates is apparently due to a synergistic immunoregulatory effect induced by the RATG and donor BM. The model described is apparently the first report of long-term survival of outbred higher primates without CI and may represent a technique for producing tolerance without CI in the human.