Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas.

Histopathologic prognostic factors of 295 pretreatment tumors of a total 641 neuroblastomas and ganglioneuroblastomas were studied with the use of the following proposed tumor classification. The tumors were divided into 2 groups: stroma-poor (235 cases) and stroma-rich (60 cases) according to their organizational pattern (stromal development). The stroma-poor group was classified further into 2 subgroups: favorable stroma-poor (84% survival) and unfavorable stroma-poor (4.5% survival) according to the patient's age at diagnosis, degree of maturation, and nuclear pathology [mitosis-karyorrhexis index (MKI)] of the neuroblastic cells. The stroma-rich group was further classified into 3 subgroups: well differentiated (100% survival), intermixed (92% survival), and nodular (18% survival) on the basis of morphology of the immature element in the tumor tissue without regard to patient's age or quantitative maturation. Favorable stroma-poor and well-differentiated and intermixed stroma-rich groups seem to make good prognosis groups (87% survival), which show gradual progression along a maturational sequence according to the age of the patient. Unfavorable stroma-poor and nodular stroma-rich groups form poor prognosis groups (7% survival) and show morphological evidence of malignant or aggressive behavior, such as inappropriate immaturity for age, higher MKI, and gross nodule formation by immature neuroblasts.

Relationship of tumor-cell ploidy to histologic subtype and treatment outcome in children and adolescents with unresectable rhabdomyosarcoma.

Clinical and histopathologic features are often inadequate for accurate prediction of relapse or survival of individual patients with rhabdomyosarcoma (RMS). We therefore studied the cellular DNA content (ploidy) of RMS cells in relation to histology and response to therapy in 37 patients with unresectable tumors. Using flow cytometric techniques, we found that about one third of patients had diploid tumor stem lines, regardless of the histologic subtype. In the group with abnormal ploidy, a hyperdiploid classification (1.10 to 1.80 times the DNA content of normal diploid cells) was exclusively associated with embryonal histology (P = .001). By contrast, near-tetraploidy (1.80 to 2.60 times the DNA content of normal cells) was strongly associated with alveolar histology (P = .001). Thus, in these histologic subtypes of RMS, abnormal ploidy appears to arise through different mechanisms. Tumor-cell ploidy had a significant impact on survival that was especially apparent in patients with unresectable, nonmetastatic (group III) tumors. In this subgroup, hyperdiploidy conferred the best prognosis and diploidy the worst (P less than .0001). None of the eight patients with diploid tumors survived for more than 18 months. Tumor-cell ploidy was the best predictor of treatment outcome for patients with either embryonal (P less than .001; relative risk, 25.5) or alveolar (P = .073; relative risk 7.1) RMS and contributed significantly after adjustment for disease stage and anatomic site. Patients with unresectable diploid RMS have an unacceptably high risk of treatment failure, justifying new therapeutic approaches for this distinct subgroup.

Histopathology of childhood sarcomas, Intergroup Rhabdomyosarcoma Studies I and II: clinicopathologic correlation.

Histopathologic material from 1,782 patients registered in the Intergroup Rhabdomyosarcoma Study Committee (IRS)-I and -II were reviewed by the IRS Pathology Committee in order to provide a uniform approach to classification and correlate patient survival with tumor type. Categories considered eligible were the four types of rhabdomyosarcoma (RMS) (criteria of Horn and Enterline), extraosseous Ewing's tumor (EOE), and a group of somewhat variable undifferentiated sarcomas designated small round cell sarcoma, type indeterminate (STI). Tumors that were clearly sarcomas but were unclassifiable also were included (NOS). The committee diagnoses were embryonal (Emb) RMS in 877 (54%), alveolar (Alv) RMS in 343 (21%), botryoid (Botr) RMS in 88 (5%), pleomorphic (Pleo) RMS in 11 (1%), STI in 135 (8%), and EOE in 84 (5%). One in nine were mixtures of types, eg, Emb and Alv. Five percent of the sarcomas could not be classified because of inadequate material. In general, there was close agreement (94%) between the review committee and institutional pathologists in the diagnosis of RMS, but not in the specific types, particularly Alv RMS (41%) and STI (36%). This observation is important, since patients with Alv RMS and STI tumors had decreased survival compared with the other histologies. The prognosis varied by histology, with Botr having the best, Alv RMS and STI the worst, and Emb RMS and EOE an intermediate prognosis.

Tumor-cell DNA content predicts outcome in children and adolescents with clinical group III embryonal rhabdomyosarcoma. The Intergroup Rhabdomyosarcoma Study Committee of the Children's Cancer Group and the Pediatric Oncology Group.

PURPOSE: The prognostic value of tumor-cell DNA content (ploidy) was evaluated in children with unresectable, nonmetastic rhabdomyosarcoma of embryonal histology. PATIENTS AND METHODS: Flow-cytometric techniques were used to estimate the ploidy of tumor specimens from 34 patients with embryonal rhabdomyosarcoma who were enrolled in the intergroup rhabdomyosarcoma study III (IRS III) from 1985 to 1991. Tumors were classified as diploid or hyperdiploid (DNA content, 1.1 to 1.8 times that of normal diploid cells). The influence of ploidy on clinical outcome was assessed by the Kaplan-Meier technique and Cox regression analysis with stepwise selection. RESULTS: Twelve of the tumor specimens were diploid and 22 were hyperdiploid. The patient groups defined by diploid or hyperdiploid tumors had similar presenting characteristics (eg, age, tumor size, and anatomic site). Significantly more children with hyperdiploid tumors achieved a complete response than did children with diploid tumors (85% v 42%; P = .01). The probability of progression-free survival at 5 years (+/- SE) was 91% +/- 6% for the hyperdiploid group, compared with 17% +/- 11% for the diploid group (P < .001). Hyperdiploidy was also associated with a significantly higher overall survival rate at 5 years: 96% +/- 4% versus 50% +/- 14% (P = .004). Ploidy retained its prognostic significance after adjustment for tumor site in the Cox regression model. CONCLUSION: Tumor-cell ploidy strongly correlates with outcome in children with nonmetastic, unresectable embryonal rhabdomyosarcoma. The two biologically distinct groups identified by this measure would benefit from further refinements in risk-directed therapy.

Second malignant neoplasms in children treated for rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee.

PURPOSE: This study was performed to determine the incidence and risk factors involved in the development of a second malignant neoplasm (SMN) after treatment of primary rhabdomyosarcoma (RMS) in patients enrolled onto Intergroup Rhabdomyosarcoma Studies I and II (IRS I and II). PATIENTS AND METHODS: There were 1,770 patients with primary RMS entered onto IRS I and II between 1972 and 1984. They were treated with chemotherapy and, in most instances, radiotherapy according to randomized or assigned regimens based on clinical grouping. Median follow-up time for these patients was 8.4 years. Incidence density (ID) was calculated for each study and for treatment and age groups. The 10-year cumulative incidence was estimated for each study. RESULTS: Twenty-two SMNs have been reported through 1991. The most common tumor type was a bone sarcoma followed by acute nonlymphoblastic leukemia (ANLL). The median time to the development of an SMN was 7 years (range, 1 11/12 to 15 9/12 years). The 10-year cumulative incidence rate was 1.7% for both studies. ID and cumulative incidence estimates were highest for patients who received both an alkylating agent and radiotherapy. The majority of patients for whom family histories were available had either neurofibromatosis themselves or a family history that suggested the Li-Fraumeni syndrome (LFS). CONCLUSION: The results of this study suggest that genetic abnormalities play a prominent role in the development of an SMN after therapy for a primary RMS. Chemotherapy with an alkylating agent and radiotherapy play significant roles in the development of an SMN compared with patients who received only one of these therapeutic modalities.

Preservation of the bladder in patients with rhabdomyosarcoma.

PURPOSE: To review the pathologic findings from children with gross residual rhabdomyosarcoma (RMS) of the bladder and compare the treatment outcome of those who underwent cystectomy with those who did not. PATIENTS AND METHODS: Primary and follow-up records and pathology specimens for 28 patients with gross residual disease entered onto the intergroup Rhabdomyosarcoma Study (IRS) III were reviewed. These patients were assigned to receive 20 weeks of multiagent induction chemotherapy and 4 weeks of radiotherapy. Future therapy decisions were based on clinical and histologic evaluation at 20 weeks. RESULTS: All patients had a clinical and histologic response. Thirteen patients underwent cystectomy at intervals that ranged from 1.5 to 38 months after the start of therapy. All but one patient are alive and well without recurrence. Reasons for cystectomy included presumed evidence of tumor growth from imaging studies, findings at cystoscopy, or histologic interpretation of biopsies. In 12 of 14 specimens from 15 patients who retained their bladder, no tumor cells were seen at first or second evaluation. In cystectomy specimens, tumor cellularity was markedly reduced and all tumor cells were in varying degrees of cellular maturation. Review of primary tumor specimens showed a greater degree of cellular maturation in patients with retained bladders than in those who underwent cystectomy. CONCLUSION: Bladder RMS is responsive to chemotherapy and radiotherapy. Twelve of 26 patients showed complete loss of tumor cells after induction therapy. Cystectomy specimens showed diminished tumor cells with varying degrees of cellular maturation. It is hypothesized that these tumors may have shown further maturation and ultimate loss of matured cells with continuing therapy.

Ewing's sarcoma of soft tissues in childhood: a report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991.

PURPOSE: One hundred thirty of 2,792 patients (5%) registered on three Intergroup Rhabdomyosarcoma Study clinical trials (IRS-I, -II, and -III) from 1972 to 1991 had an extraosseous Ewing's sarcoma (EOE). We report here the results of multimodality therapy for this tumor. PATIENTS AND METHODS: The 130 patients were less than 21 years of age; 70 (54%) were males. Primary tumor sites were on the trunk in 41 patients, an extremity in 34, the head/neck in 23, the retroperitoneum/pelvis in 21, and other sites in 11. One hundred fourteen patients had no metastases at diagnosis. In 21 patients, the tumor was completely resected; in 30, the localized or regional tumor was grossly resected, and in 63 patients, grossly visible sarcoma was left behind. Sixteen patients (12%) had distant metastases at diagnosis. All patients were given multiagent chemotherapy and most received irradiation (XRT); none were treated with bone marrow transplantation. RESULTS: One hundred seven patients (82%) achieved a complete response. At 10 years, 62%, 61%, and 77% of the patients were alive after treatment on IRS-I, IRS-II, or IRS-III therapeutic protocols, respectively, similar to figures obtained in all IRS patients. At last follow-up evaluation, 42 patients had died of progressive tumor and one of infection. Survival at 10 years was most likely for patients with tumor that arose in the head and neck, extremities, and trunk, and for those who underwent grossly complete tumor removal before initiation of chemotherapy. For patients with localized, gross residual tumor, adding doxorubicin (DOX) to the combination of vincristine, dactinomycin, cyclophosphamide (VAC), and XRT did not significantly improve survival in 39 patients (62% alive at 10 years) compared with that of 24 patients treated with VAC and XRT without DOX (65% alive at 10 years, P = .93). CONCLUSION: This series indicated that EOE in children is similar to rhabdomyosarcoma (RMS) in its response to multimodal treatment. No benefit was apparent from the addition of DOX to VAC chemotherapy in patients with gross residual EOE.

Rhabdomyosarcomas with intermediate-filament inclusions and features of rhabdoid tumors. Light microscopic and immunohistochemical study.

A group of 27 rhabdomyosarcomas (RMS) whose histology showed abundant cells containing cytoplasmic intermediate-filament globular inclusions resembling those seen in rhabdoid tumors has been identified among Inter-group Rhabdomyosarcoma Study (IRS) I-III patients (less than 1%). Their histologic subtype was embryonal RMS in 22 and alveolar RMS in 5. One-half of tumors occurred in deep muscles of the extremities, retroperitoneum, or in the pelvis. Immunohistochemical analysis of 12 cases showed the inclusions to be vimentin or desmin positive. Anti-muscle-specific actin antibodies were positive in the cytoplasm of 11 cases, but not in the site of the intermediate-filament inclusions. Seven poorly differentiated neoplasms closely resembled rhabdoid tumors and possessed large nucleoli in most cells along with cytoplasmic inclusions. In contrast to true rhabdoid tumors, their nuclear chromatin was usually coarse. Immunohistochemistry proved useful in distinguishing tumors with early myoblastic differentiation. A positive anti-desmin, when confined to the cytoplasmic inclusions only, should be complemented with other muscle-specific antibodies, especially anti-muscle actin to separate RMS from rhabdoid tumors. The statistical analysis was limited by the small number of cases, but there was no statistical difference in survival when this group of RMS was compared with 996 IRS-II patients as a whole. The distinction of RMS with abundant intermediate-filament inclusions from rhabdoid tumors is of clinical importance because patients with true rhabdoid tumors have a highly unfavorable prognosis.

Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study.

The pleomorphic subtype of rhabdomyosarcoma (RMS) is now rarely diagnosed in both children and adults. Most cases previously called pleomorphic RMS are probably diagnosed as something else, most often embryonal RMS in children and malignant fibrous histiocytoma in adults. To analyze the concept of pleomorphic RMS in children, we reviewed the tumors of patients entered on the Inter-group Rhabdomyosarcoma Study (IRS I, II, and III). The presence of cells with lobated, hyperchromatic nuclei at least three times larger than the common tumor cell population (anaplastic cells) was selected as the main criterion. Of about 3,000 cases, 110 showed these types of cells, had sufficient histologic material, and had available follow-up data. These tumors were divided into two subgroups: Subgroup I tumors contained only scattered anaplastic cells, and tumors with foci or large sheets of anaplastic cells were classified as subgroup II. Besides the anaplastic-pleomorphic areas, most of these tumors had distinctive features of embryonal RMS (105 cases) and rarely had characteristics of alveolar RMS (five cases). The age distribution of these patients did not differ significantly from those whose tumors did not show the anaplastic features, the average being 6 years and the median 4 years. Lower extremity, retroperitoneum, and the head and neck region were the most common primary tumor sites. The 5-year survival rate was 60% for subgroup I tumors and 45% for subgroup II tumors compared with the survival rate of 68% for 482 IRS II embryonal RMS cases with no anaplastic-pleomorphic features. The lower survival rate for patients in subgroup II was statistically significant (p = 0.004) and similar to the unfavorable survival of patients with alveolar RMS and undifferentiated sarcoma. Because anaplastic cells are seen in many soft tissue sarcomas and in both embryonal and alveolar RMS in children, this feature is not sufficiently unusual to separate a pleomorphic subtype of RMS. The presence of anaplastic cells in aggregates or diffuse sheets throughout the tumor, however, portends a poor survival for these patients.

Spindle cell variants of embryonal rhabdomyosarcoma in the paratesticular region. A report of the Intergroup Rhabdomyosarcoma Study.

We reviewed 173 cases of paratesticular rhabdomyosarcoma (RMS) of Intergroup Rhabdomyosarcoma Studies (IRS)-I, -II, and -III for evaluation of possible histological factors that might account for the good prognosis of these patients. Almost all cases (161 of 173 cases, 93.1%) occurring in this site were of embryonal histology. A spindle-cell subtype of embryonal RMS was identified that presented a storiform growth pattern with abundant collagen between the tumor cells in most cases. Other tumors of this subtype showed an arrangement of tumor cells in bundles with a low to moderate amount of collagen, resembling a leiomyosarcoma. The other embryonal RMS in this site had the classical embryonal cytology. The spindle-cell subtype was highly differentiated by immunohistochemistry and electron microscopy. Lymph node metastasis was found in seven of 43 patients (16.3%) with a RMS of spindle-cell subtype, compared with 40 of 112 patients (35.7%) with RMS of non-spindle-cell type. Clinical data from patients with spindle-cell subtypes of the paratesticular lesions revealed that they almost always had an association with clinical groups of limited disease (32 patients, 74.4%, with Group I; 10 patients, 23.3%, with Group II disease) and a significantly better prognosis (95.5% survival at 5 years) when compared with patients with the classic embryonal variant of RMS (80% survival at 5 years, p < 0.035). The incidence and anatomic distribution of this spindle cell subtype of embryonal RMS was estimated on 800 randomly selected patients from IRS-II. It was found in the head and neck, extremities, orbit, and some other sites, but 30.6% were located in the paratesticular area. Patients with spindle cell RMS of nonparatesticular sites usually had more extensive disease compared with patients having paratesticular lesions; two thirds of the cases had gross residual tumor after surgery or metastatic tumor at diagnosis. We conclude that spindle-cell RMS is a subtype of embryonal RMS with a very favorable prognosis. The site factor of the paratesticular localization may allow earlier diagnosis of the spindle-cell lesions compared with other sites. Other unknown factors may also play a role.

Pseudosarcomatous myofibroblastic tumor of the urinary bladder in children: a study of 11 cases with review of the literature. An Intergroup Rhabdomyosarcoma Study.

Pseudosarcomatous myofibroblastic tumor (PMT) is the result of reactive proliferation of myofibroblasts. In children, PMT of the urinary bladder can be mistaken for embryonal rhabdomyosarcoma clinically, radiologically, and by light microscopy. We are reporting the clinical, histological, and immunohistological features of 11 patients with childhood PMT of urinary bladder that were diagnosed initially as a sarcoma, usually rhabdomyosarcoma. The morphologic spectrum of PMT is broad, with mixtures of myxoid, leiomyomatous, and sclerosing matrix patterns, the myxoid type being the most common. The proliferating cells consist of three forms of myofibroblastic cells: long spindle cells (type I), intermediate spindle cells (type II), and ganglion-like cells (type III), together with various types of inflammatory cells. The immunohistologic profile of the proliferating cells was characterized by positive reactions to vimentin, muscle-specific actin, alpha-smooth-muscle actin, polyclonal desmin, and keratin. Ultrastructural studies showed myofibroblastic differentiation of the tumor cells. No patients have had metastases or local recurrence. Histologic, immunohistochemical, and clinical data from 71 cases of PMT, including the 11 cases in this report, confirm the benign behavior of these lesions. The etiology of these lesions is unclear, including the absence of surgical or other trauma in all of the children.

Prognostic subgroups for undifferentiated neuroblastoma: immunohistochemical study with anti-S-100 protein antibody.

Pathologic prognostic factors in 36 undifferentiated neuroblastomas were studied by an immunohistochemical staining technique with anti-S-100 protein antibody. Nuclear abnormalities of neuroblastic cells (mitosis and karyorrhexis/5,000 cells [MKI]), the incidence of S-100 protein-positive cells in the supportive stroma, and the age of the patients at diagnosis were analyzed both individually and in combination. Based on the evaluation of these factors, two prognostic subgroups were identified for these tumors. Tumors for which the prognosis was good (all nine patients alive) occurred in younger patients (younger than 1.5 years), showed low (less than 100) or intermediate (100 to 200) MKI, and had positive to intensely positive staining for S-100 protein. Cases in which the prognosis was poor (7 per cent survival) had single or multiple factors of high (greater than 200) MKI and/or absent or weak staining for S-100 protein and/or older age (older than 1.5 years) at diagnosis. These results were compared with other clinical information.

Pathologic features of extraosseous Ewing's sarcoma: a report from the Intergroup Rhabdomyosarcoma Study.

Eighty-four cases of extraosseous Ewing's sarcoma (EOE) were found during the pathology review of the Intergroup Rhabdomyosarcoma Study I and II. Patients commonly presented during or after adolescence with the most common primary sites including the trunk, extremities, and retroperitoneum. Males were slightly more affected. Histologic sections of 74 tumors in the pathology repository were re-reviewed with attention to rosette formation (positive in 18 cases) and glycogen deposition (++ in 21, + in 36, +/- in 11, and - in 2 of 70 cases examined). Fourteen tumors (7 with rosettes and 7 without) were selected for immunohistochemical and ultrastructural studies, and 13 showed single or multiple neural markers (neuron-specific enolase in 8, S-100 protein in 6, and neurosecretory-type granules in 9). These possible cases of neural EOE could be divided into three subgroups: tumor with bidirectional neuroblastic and schwannian differentiation (5 cases), tumor with monodirectional neuroblastic differentiation (7 cases), and tumor with monodirectional schwannian differentiation (1 case). EOE with a neural nature may be categorized into a spectrum of peripheral primitive neuroectodermal tumors. Clinical, histopathologic, and biologic differences between this disease and conventional sympathetic neuroblastoma are discussed.

Rhabdoid tumors of soft tissues: a clinicopathologic study of 26 cases enrolled on the Intergroup Rhabdomyosarcoma Study.

Twenty-six cases of malignant soft tissue tumors with features similar to renal rhabdoid tumors were identified among approximately 3,000 childhood sarcomas entered on Intergroup Rhabdomyosarcoma Studies I-III. The tumors consisted of polygonal cells with vesicular nuclei and prominent nucleoli and cytoplasmic intermediate filament inclusions as identified by electron microscopy and immunohistochemistry. The growth pattern was predominantly solid or solid-trabecular. Immunohistochemistry showed vimentin, wide spectrum keratin, and epithelial membrane antigen to be the most consistent antigenic phenotypes. Eleven patients were infants less than 1 year of age. The tumors affected predominantly soft tissues of proximal extremities, trunk, and retroperitoneum/pelvis/abdomen. Nineteen patients died within 1 to 82 months (median, 6 months) from the start of treatment. Five patients have survived the disease for 2 to 13 years. When compared with the survival analysis of 991 Intergroup Rhabdomyosarcoma Study II patients, it was obvious that this group of tumors fares very poorly (P less than .001). The tumor belongs to the group of soft tissue neoplasms showing mesenchymal and subtle epithelial differentiation, similar to epithelioid sarcoma. Because of its identifiable histology, site and age distribution, and poor outcome, it warrants a status as an independent entity.

Reasonable surgery for thoracic neuroblastoma in infants and children.

Neuroblastoma is the most commonly encountered soft tissue malignant tumor of childhood. Over the past 30 years we have treated 180 patients with neuroblastoma. Sixty-five percent had primary abdominal tumors and 20 percent (41 patients) had primary chest tumors. For the 22 patients under the age of 2 years, the 2 year survival rate was 87 percent. There were 19 patients who were 2 years of age or older, and of these only seven patients have survived 2 years after the diagnosis was made. The vast majority of these patients were treated with surgery (debulking type procedure) and postoperative radiation and chemotherapy. Patients with the most differentiated tumors had a remarkably good survival rate, with no deaths. However, the tumors with lesser differentiation did not stratify enough focus to draw conclusions as to survival. Staging correlated the least with survival when compared to age or grading. The 2 year survival rates for patients with Stage I, II, III, IV, and IV-S disease were 75, 82, 100, 17, and 80 percent, respectively. In conclusion, 41 cases of documented primary thoracic neuroblastoma are reviewed, with follow-up from 2 to 27 years (average 9.3 years). We have concluded from this experience that age is the main determining factor influencing survival. Heroic and/or radical surgery is contraindicated in this disease.

Specific expression of insulin-like growth factor-II in rhabdomyosarcoma tumor cells.

Insulin-like growth factor II (IGF-II) acts as autocrine growth and motility factor in human rhabdomyosarcoma cell lines, and Northern blot analysis of tumor biopsy specimens from both alveolar and embryonal rhabdomyosarcoma demonstrates high levels of IGF-II mRNA expression. To determine the frequency and site of expression of IGF-II in these tumors, the authors performed in situ hybridization. All tumor specimens examined expressed the gene for IGF-II, and this expression was localized to the tumor cells themselves and not to the surrounding stroma. These data suggest that the IGF-II autocrine loop may be operating not only in vitro but also in vivo.

Thymic changes in histiocytosis.

In order to arrive at a hypothesis of the pathogenesis of thymic changes in histiocytosis, the thymus glands from thirty-two children with histiocytosis were studied. In general, the changes were a severe loss of cortical and medullary structures rather than stress type changes in which only the cortical structure changes. The thymic changes were then classified into three main groups: severe dysplasia equivalent to that seen in congenital immune deficiency, severe nonspecific involution, and a third group designated as a dysmorphic type which resembled those with dysplasia, but, in addition, showed smaller lobules and interstitial histiocytic infiltration. The thymic changes correlated with the type of histiocytic disease. For the purposes of this study, the disease was categorized as Type I or Type II, as previously described. Dysplastic changes were only seen in those patients with Type I histiocytic disease, while involution occurred in patients with Type II histiocytic disease. Dysmorphic change was apparent in both, but it had a much higher incidence in Type II.

New look at mesoblastic nephroma.

Thirty eight mesoblastic nephromas were studied. The age range of the patients was between the neonatal period and 18 months. The presence of cartilage is consistent with a mesoblastic origin, but squamous epithelium was a feature in three tumours. Particular attention was given to the adjacent renal tissue in which various histological features were noted: vacuolated and dysplastic tubules; cysts; and subcapsular epithelial tumourlets. The findings had aspects in common with both dysplastic kidneys and nephroblastoma. Classification of the tumours as normocellular and hypercellular was attempted, but there was considerable overlap. The behaviour of the tumour was good in all cases, although follow up was relatively short on some patients, and deaths from non-neoplastic causes occurred.

Role of the thymus in histiocytosis-X.

An increasing number of reports have demonstrated that patients with histiocytosis-X show significant morphologic changes in the thymus gland. The changes include severe dysplasia, dysmorphia, and severe nonspecific involution. These findings are present in all children with histiocytosis-X who die, but can be found even when the disease is limited to one bone and is not fatal.

Portal hypertension in infants and children with histiocytosis X.

Histiocytosis X describes a disease characterized by histiocytic infiltration of the reticuloendothelial system, skin, bones, and pituitary gland. The disseminated form frequently occurs in infants and children. Chemotherapy has significantly improved the prognosis in this disorder. Sixty-three per cent of survivors, however, have some residual disability related to fibrosis of tissues previously infiltrated by histiocytes. In instances of liver involvement, healing by fibrosis may result in cirrhosis with portal hypertension and bleeding esophageal varices. Clinical findings include hepatosplenomegaly, jaundice, ascites, hypoalbuminemia, prolonged prothrombin time, and Bromsulphalein retention. Histologic examination of the liver shows a characteristic dense "macronodular" periportal cirrhotic pattern. Three children with portal hypertension and bleeding varices due to healed histiocytosis X were sucessfully managed by portosystemic shunt procedures. Portacaval, mesocaval, and central splenorenal shunts were equally effective in relieving poral hypertension. These children had neither recurrence of bleeding nor evidence of encephalopathy. Two children remain well whereas in one patient a primary hepatoma developed fourteen years posthung and he died of pulmonary metastases. Portosystemic shunt procedures effectively relieve the threat of potentially fatal variceal hemorrhage and improve the opportunity for long-term survival in children with cirrhosis and portal hypertension due to healed histiocytosis X.