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V V Joshi

Publications and source records attributed to V V Joshi.

At least 19 recordsLinked to original sources
PubMed1996

Modified histologic grading of neuroblastomas by replacement of mitotic rate with mitosis karyorrhexis index. A clinicopathologic study of 223 cases from the Pediatric Oncology Group.

BACKGROUND: Histologic grading (HG) of neuroblastomas (NB) of prognostic significance is based on the presence of absence of calcification and low mitotic rate ( < or = 10/10 high power fields). Mitosis karyorrhexis Index (MKI) is the main feature used for prognostic categorization in Shimada classification and can be determined more readily than mitotic rate (MR). The purpose of this study is to test whether MKI can be used instead of MR for histologic grading. METHODS: Low and intermediate MKI were lumped together as low MKI. We replaced MR with the modified MKI categories. Histologic grades for 223 NBs registered with the Pediatric Oncology Group protocols 8104 and 8441, were defined ad follows: HG 1 = calcification + low MKI, HG 2 = calcification or low MKI, HG 3 = high MKI and absence of calcification. Shimada classification was also determined for comparison or modified HGs with favorable histology (FH) and unfavorable histology (UH), HGs were linked with age: low risk (LR) = HG 1 in all age groups + HG 2 in patients age younger than 1 year; high risk (HR) = HG 2 in patients age 1 year of older + HG 3 in all age groups. RESULTS: Statistically significant differences in 5-year survival were seen in the NBs of different modified HG (1: 92.7%, 2: 74.9%, and 3: 18.2%) and risk groups (LR 93.0% and HR 47.9%) (P < 0.0001 and P = 0.0001, respectively). CONCLUSIONS: Pathologists may readily adapt to the modified HG described here. Advantages of modified HGs include: (1) familiarity and reproducibility of MKI; (2) no need for linkage with age; and (3) a combination of features used in original HGs and Shimada classification.

Child↗
PubMed1995

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.

Chi-Square Distribution↗
PubMed1995

Lack of correlation of N-myc gene amplification with prognosis in localized neuroblastoma: a Pediatric Oncology Group study.

Multiple copies of N-myc proto-oncogene are only rarely detected in localized neuroblastomas (NBs), and the prognostic relevance of amplification in this subset of patients is not clear. We analyzed a series of 850 children with NB admitted to a Pediatric Oncology Group NB Biology Study and identified six patients with localized NBs harboring N-myc gene amplification. Three patients whose tumors showed favorable histology by Shimada classification and low-risk histological features according to the Joshi classification have remained disease-free, whereas two of three patients with unfavorable histology tumors have developed recurrent disease. Although earlier studies have indicated that N-myc amplification is associated with diploid DNA content, flow cytometric analysis revealed that only two of the localized tumors contained stem lines with diploid DNA content. Loss of chromosome 1p was not detected by fluorescence in situ hybridization in the two tumors examined. N-myc protein was detected by immunohistochemical studies in four of the five NBs analyzed. However, N-myc protein was not visualized in one of the tumors with stroma-rich histology, and Western blot analysis revealed only low levels of N-myc protein expression in another NB with favorable histology. These studies indicate that the presence of N-myc amplification in localized NBs does not necessarily portend an adverse outcome. Furthermore, the biological features of this subset of N-myc-amplified NBs appear to differ from those of more advanced N-myc-amplified tumors.

Child↗
PubMed1995

Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS.

BACKGROUND: Children with the acquired immunodeficiency syndrome (AIDS) have an unusually high incidence of smooth-muscle tumors (leiomyomas and leiomyosarcomas) in addition to malignant lymphomas. We tested the hypothesis that the smooth-muscle tumors in these children are associated with the Epstein-Barr virus (EBV). METHODS: Tissue specimens of five leiomyosarcomas and two leiomyomas from six children with AIDS were studied for evidence of the human immunodeficiency virus (HIV) and EBV by in situ hybridization and quantitative polymerase chain reaction (PCR). Comparison specimens included samples of leiomyosarcoma and leiomyoma from HIV-negative children. EBV clonality of leiomyosarcomas was determined by Southern blot analysis with oligonucleotide probes for EBV terminal-repeat fragments. Tumor specimens were tested by immunoperoxidase staining for infiltration by B lymphocytes and expression of the EBV receptor. Serologic testing for EBV was performed. RESULTS: In situ hybridization showed EBV genomes in all muscle cells of the five leiomyosarcomas and the two leiomyomas from the six HIV-infected children. Quantitative PCR demonstrated strikingly high levels of EBV in tumor tissue, with as many as 4.3 genome copies per cell. Two colonic leiomyosarcomas obtained from different sites at different times from one patient contained different episomal EBV clones, signifying the presence of distinct monoclonal EBV-related tumors. We found biclonal EBV infection in the leiomyosarcoma of another patient. No EBV was detected in normal muscle or tumor specimens from HIV-negative patients. Immunostaining for the EBV receptor was strongly positive in six of the seven leiomyomas and leiomyosarcomas from the patients with AIDS. CONCLUSIONS: EBV can infect smooth-muscle cells, at least in patients with AIDS, and it may contribute to the pathogenesis of leiomyomas and leiomyosarcomas in children with AIDS. EBV seems to play no part in smooth-muscle tumors in HIV-negative children.

AIDS-Related Opportunistic Infections↗
PubMed1995

Effusion cytology in Burkitt's lymphoma.

The American form of Burkitt's lymphoma is a high-grade malignancy which usually involves the abdomen in children and young adults. There is only a limited literature which describes the cytologic features of Burkitt's lymphoma in serous effusions. We present three children with Burkitt's lymphoma initially diagnosed by effusion cytology. The first patient, an 11-yr-old boy, presented with bilateral pleural effusions, ascites, and abdominal masses and had diagnostic pleural fluid cytology without tissue confirmation (ultrastructural examination was performed on the effusion specimen). He died 7 months after the initial diagnosis. The second patient, a 9-yr-old boy, presented with ascites and abdominal masses and had diagnostic peritoneal fluid cytology with a subsequent confirmatory chest wall biopsy. The third patient, a 16-yr-old girl, presented with a 2-month history of irregular menses, a large pelvic mass, lymphadenopathy, and liver masses. Although an ovarian malignancy was clinically suspected, cytologic examination of her peritoneal fluid revealed Burkitt's lymphoma. Surgical exploration revealed involvement of her right ovary, cecum, and terminal ileum. The second and third patients are currently alive with no apparent disease following chemotherapy. In all three patients, effusion cytology revealed Burkitt's lymphoma, characterized by a uniform population of non-cohesive lymphoid cells with noncleaved nuclei, prominent multiple nucleoli, and scanty-to-moderate basophilic cytoplasm. Cytoplasmic and/or nuclear vacuoles were also seen, more prominent in Diff-Quik-stained, air-dried smears. These cases demonstrate the importance of recognizing the cytologic features of Burkitt's lymphoma, as serous fluid may be the initial diagnostic specimen.

Adolescent↗
PubMed1995

Reversal of Indian childhood cirrhosis by D-penicillamine therapy.

Serial liver biopsy changes have been reviewed in 30 patients with Indian childhood cirrhosis (ICC) who were randomly allocated to receive treatment with penicillamine in a dose of 20 mg/kg/day, 10 of whom also received prednisolone, and five receiving placebo. The latter died within 185 (mean, 149) days of starting treatment. Nine receiving penicillamine died within 540 (mean, 338) days, but the remainder are well 5.1-9.3 years after commencing treatment. Initial biopsies showed severe hepatocellular injury, pericellular fibrosis, inflammatory infiltration, and orcein-staining granules. Second biopsies taken within 6 months of starting penicillamine usually showed persistence of inflammation and an increase in nodularity with thick and thin active septae. Subsequently the appearances were of an inactive micronodular cirrhosis, with reduction in septal inflammatory infiltrate, hepatocellular injury, and intensity of orcein staining. This further improved to a stage of incomplete fibrous septae. The last liver biopsies at 6-60 months (in 21 survivors) showed almost normal histology in four, incomplete fibrous septae in five, and inactive micronodular cirrhosis with thin septae in 12. Mean liver copper concentrations decreased from 1,407 (SEM, 121) micrograms/g at presentation to 925 (183), 317 (100), and 127 (35) at 6, 6-18, and > 18 months after starting treatment. By contrast, a second biopsy taken in the 6 months after diagnosis in placebo-treated children showed persistence of ICC with increase in inflammation, fibrosis, and orcein staining.

Biopsy↗
PubMed1994

FNA biopsy of small round cell tumors of childhood: cytomorphologic features and the role of ancillary studies.

Pediatric tumors which are conventionally considered to be small round cell tumors (SRCTs) include the prototypical neuroblastoma as well as rhabdomyosarcoma (RMS), Ewing's sarcoma (ES), malignant lymphoma, and primitive neuroectodermal tumor (PNET). Other malignancies may be considered in the differential diagnosis such as small-cell osteogenic sarcoma, undifferentiated (anaplastic) hepatoblastoma, granulocytic sarcoma, blastemal type Wilms' tumor, and desmoplastic small-cell tumor of the peritoneum. The cytomorphologic features of conventional SRCTs is presented as well as the utility of ancillary studies performed on the aspirated material in making a specific and correct diagnosis. The role of the immediate cytologic assessment of the aspirate is stress, since this is a critical step in formulating an initial diagnostic impression that should prompt the need for additional material for pertinent ancillary studies. Although challenging, FNA cytology of SRCTs of childhood can be diagnostic in the majority of cases, allowing specific therapy to be given to patients with unresectable SRCTs without a tissue biopsy as well as documenting recurrent and/or metastatic disease.

Adolescent↗
PubMed1994

Pathology of neuroblastic tumors.

Histogenesis, basic histologic features, nomenclature, and criteria for diagnosis and prognostic classifications based on morphological features of neuroblastic tumors (NTs) are described. NTs that arise from neuroectodermal cells of the adrenal medulla and sympathetic ganglia recapitulate the development of sympathetic ganglion. The following three basic types of NTs are recognized: neuroblastoma (NBs) and ganglioneuroblastomas (GNBs) and ganglioneuromas (GNs). NBs can be undifferentiated, poorly differentiated or differentiating; GNBs have the following three subtypes. (1) nodular, (2) intermixed, and (3) borderline. The conventional and recommended terminology and Shimada terminology of NTs are described (Tables 1 and 2). There are three basic pathologic components of NTs, neuroblastomatous, ganglioneuromatous, and intermediate components (Figs 3, 5, and 7). There are two major prognostic classifications based on morphological features of NTs, Shimada classification and histologic grading (Tables 3 and 4).

Adrenal Gland Neoplasms↗
PubMed1994

Veno-occlusive disease of the liver induced by low-dose cyclophosphamide.

A 2-yr-old child with idiopathic pulmonary hemosiderosis and autoimmune thrombocytopenia developed hepatic veno-occlusive disease after being treated with long-term, low-dose cyclophosphamide. The authors believe that the injury was induced by cyclophosphamide. Although transplant dosages of cyclophosphamide alone or in conjunction with other drugs have been shown to induce hepatic venocclusive disease, this is the first case of hepatic venocclusive disease associated with nontransplant dosages of cyclophosphamide. Histopathologically, the injury was characterized by occlusive lesions of intrahepatic veins, both the terminal hepatic venules and portal veins branches, together with necrosis (predominately involving Zones 3 and 2) and hemorrhages. An added risk factor could have been release of platelet-derived growth factor that in turn activated and promoted proliferation of fibroblasts and smooth muscle cells in the vessels. Previously reported cases of cyclophosphamide-related injury are reviewed.

Child, Preschool↗
PubMed1993

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.

Adolescent↗
PubMed1993

Cytomorphology of familial hemophagocytic syndrome.

Familial hemophagocytic syndrome (FHS) is a rare, fatal disorder of childhood demonstrating failure to thrive, fever, hepatosplenomegaly (HSM), recurrent infections, pancytopenia, and histologically, the infiltration of reticuloendothelial organs by benign-appearing histiocytes demonstrating hemophagocytosis. We report two fatal cases of FHS including a 3 year-old female who underwent fine-needle aspiration (FNA) biopsy of the liver in the initial workup of the disease (case 1) and an 8 month-old boy with ascites and HSM having peritoneal fluid cytology submitted as the first specimen for morphologic examination (case 2). In case 1, the FNA cytologic findings included benign hepatocytes and scattered mature and reactive lymphocytes and histiocytes. The histiocytes demonstrated fine to coarse cytoplasmic vacuoles and erythrophagocytosis. The diagnosis was confirmed at autopsy which revealed extensive lymphohistiocytic infiltrates in various organs including the central nervous system. In case 2, the peritoneal fluid cytology specimen contained numerous atypical and degenerating mononuclear lymphoreticular cells which were dispersed as a single cell suspension admixed with infrequent mesothelial elements; hemophagocytosis was not appreciated. Subsequent liver biopsy revealed portal tracts and sinusoids infiltrated by benign but atypical histiocytes with hemophagocytosis. Bone marrow examination and then autopsy confirmed the diagnosis of FHS. A panel of immunocytochemical studies was performed in the first case which was an aid in confirming the diagnosis of FHS and ultrastructural examination of the second case revealed well-developed erythrophagocytosis. Both patients had siblings who died of FHS. Although not diagnostic, cytomorphology may suggest FHS.

Ascitic Fluid↗
PubMed1993

Thoracic neuroblastoma: a Pediatric Oncology Group study.

Ninety-six patients with thoracic neuroblastoma were studied in a prospective fashion. Median age at presentation was 0.9 years. Forty-eight percent of the patients presented with stage A disease, 20% stage B, 13% stage C, 17% stage D, and 2% stage DS. Seventy-five patients have been followed for greater than 4 years. A posterior mediastinal mass was diagnosed on incidental chest roentgenograms performed for nontumor-related symptoms in 49% of the cases. Sixteen percent of the cases presented with neurological symptoms and 14% of the patients presented with acute respiratory distress. Urinary catecholamines were elevated in 76% of the cases. Complete surgical resection was carried out in 47% of the cases, while incomplete resection or biopsy was performed in 45%. No operation was performed in 3 patients. Minor surgical complications occurred in 20% of the patients, and 3% of the patients had significant perioperative complications. One patient died as a complication of therapy. Overall actuarial survival was 88% at 4 years. This study confirms the favorable outcome in children with mediastinal neuroblastoma. The basic biology of thoracic neuroblastomas seems to differ from that of other sites in that the majority of patients present at a younger age with localized disease or regional lymph node metastases, and have an improved survival even after correcting for age and stage. While complete excision is recommended, if possible, radical surgical procedures are not indicated since an excellent prognosis is associated with combined modality therapy.

Age Factors↗
PubMed1993

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.

Biopsy, Needle↗
PubMed1993

Multicentric Castleman's disease in a child with prominent thymic involvement: a case report and brief review of the literature.

A fatal case of multicentric Castleman's disease (giant lymph node hyperplasia) with prominent thymic involvement in a 12-yr-old girl is presented. Multicentric Castleman's disease is a poorly understood lymphoproliferative disorder generally occurring in elderly individuals. To our knowledge, this is the first case in the English literature of multicentric Castleman's disease in a child. Thymic involvement has not been described previously in the multicentric variant or in a child. Besides the characteristic findings of Castleman's disease (CD), such as hyaline-vascular follicles and a prominent plasmacytic infiltrate, the thymus was also marked by prominent epithelial hyperplasia in the medulla. The clinical and pathologic findings are presented with a review of the literature, particularly thymic involvement in CD and CD in the pediatric population.

Biopsy↗
PubMed1992

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.

Child, Preschool↗
PubMed1992

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.

Age Factors↗