Early history of pathology studies by the Intergroup Rhabdomyosarcoma Study Group.

This review chronicles the series of publications that were the result of the willingness of pathologists and clinicians in the United States to share their pathologic materials and clinical data on patients who were placed on treatment protocols for rhabdomyosarcoma and related tumors over an extended period of time. The availability of this database enabled pathologists and clinicians to study a tumor type that is rare in individual institutions, but occurs in large enough numbers to produce valid conclusions not otherwise possible. Furthermore, young investigators were challenged by this opportunity and were able to spend the necessary time to make new observations that, in retrospect, helped direct protocol designs that produced significant improvement in patient survival. The key factor in this process is the surrender of individual scientific prerogatives to a small number of investigators. It is also important to recognize that the pathologist component of these series of contributions is only a part of the entire effort. It takes an organization of gifted, dedicated experts in many disciplines working together. The investigators who served on the Intergroup Rhabdomyosarcoma Group over a 25-year period eminently fulfilled this.

Undifferentiated sarcomas of children: pathology and clinical behavior--an Intergroup Rhabdomyosarcoma study.

Undifferentiated soft tissue sarcoma (UND-STS) is the most poorly defined tumor eligible for intergroup Rhabdomyosarcoma Studies (IRS). Recent IRS UND-STS experience was reviewed to assess the histologic characteristics and clinical behavior of undifferentiated sarcomas. Of the 1,527 patients entered on IRS-III and IRS pilot-IV, 96 had tumors classified by the IRS Pathology Committee as UND-STS. Of these, 52 had adequate histologic material for this study. After application of immunohistochemistry, 18 tumors were reclassified, mostly as embryonal rhabdomyosarcomas (RMS), primitive neuroectodermal tumors, and intraabdominal desmoplastic small found cell tumors. The remaining 34 UND-STS had a diffuse hypercellular histologic pattern made up of sheets of medium-sized cells. The tumor cells had a minimal to moderate amount of cytoplasm and a variable nuclear morphology, predominately vesicular with finely granular chromatin. Except for reactivity with antibodies against vimentin, most tumors had a negative immunohistochemical profile. The 5 year Kaplan-Meier survival estimate for patients with non-metastatic disease was 72%, a significant improvement when contrasted with patients diagnosed to have UND-STS in IRS-I and IRS-II.

Orbital rhabdomyosarcomas and related tumors in childhood: relationship of morphology to prognosis--an Intergroup Rhabdomyosarcoma study.

Children and adolescents who develop rhabdomyosarcoma (RMS) and related sarcomas in the orbit and treated on Intergroup Rhabdomyosarcoma protocols have had an extremely high cure rate. This study evaluates the possible relationship between their tumor morphologic subtypes and this high cure rate. The histology of tumors was re-reviewed from 229 of the 264 patients with tumors of the orbit, conjunctiva, and eyelids treated on Intergroup Rhabdomyosarcoma Studies (IRS I, II, III, and IV pilot protocols, and followed through July, 1992. Immunohistochemistry was applied in selected cases. Clinical correlations were done on all 264 cases including both the re-reviewed cases and those reviewed only by the IRS Pathology committee. The 5-year survival rate of 24 children with alveolar RMS was 74% (p < .001). All five infants diagnosed to have an alveolar RMS died before the age of one. Two hundred and twenty-one patients (84%) had embryonal RMS. About three-fourths of the re-reviewed embryonal RMS tumors showed only minimal rhabdomyoblastic differentiation. Thirty-one had a spindle cell RMS, two were anaplastic variants. The 5-year survival rate for patients with embryonal RMS subtypes combined was 94%, and 97% for the 144 patients with poorly differentiated embryonal RMS. In contrast, 90 of 432 IRS II patients treated for poorly differentiated embryonal RMS located in extraocular sites had a 66% survival estimate.

Brain heterotopia: choristoma of the back.

Heterotopic brain tissue, except in the head and neck region, is exceedingly rare. Mature neural tissue unexpectedly found in the subcutaneous tissues of the back of a toddler lacked an attachment to the central nervous system (CNS), and appeared to be unorganized glial tissue on pathologic evaluation. Appropriate clinical management of such lesions includes a suspicion of subcutaneous lesions near the CNS and evaluation to eliminate the presence of communication with the CNS, followed by surgical excision.

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.

Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification--an Intergroup Rhabdomyosarcoma Study.

BACKGROUND: There is a need to develop a single prognostically significant classification of rhabdomyosarcomas (RMS) and other related tumors of children, adolescents, and young adults which would be a current guide for their diagnosis, allow valid comparison of outcomes between protocols carried out anywhere in the world, and should enhance recognition of prognostic subsets. METHOD: Sixteen pathologists from eight pathology groups, representing six countries and several cooperative groups, classified by four histopathologic classification schemes 800 representative tumors of the 999 eligible cases treated on Intergroup Rhabdomyosarcoma Study II. Each tumor was classified according to each of the four systems by each of the pathologists. In addition, two independent subsamples of 200 of the 800 patients were reviewed according to the new system, so that 343 distinct patients were reviewed once, and 57 of these twice. RESULTS: A study of the survival rates of all subtypes in the sample of 800 patients led to the formation of a new system. This was tested on two independent subsets of 200 of the original cases and found to be reproducible and predictive of outcome by univariate analysis. A multivariate analysis of the 343 patients classified according to the new system indicated that a survival model including pathologic classification and known prognostic factors of primary site, clinical group, and tumor size was significantly better at predicting survival than a model with only the known prognostic factors. CONCLUSION: This new classification, termed International Classification of Rhabdomyosarcoma (ICR) by the authors, was reproducible and predictive of outcome among patients with differing histologies treated uniformly on the Intergroup Rhabdomyosarcoma II protocols. We believe it should be utilized by all pathologists and cooperative groups to classify rhabdomyosarcomas in order to provide comparability among and within multi-institutional studies.

Successful treatment of disseminated central nervous system malignant rhabdoid tumor.

PURPOSE: Malignant rhabdoid tumor (MRT) of the central nervous system (CNS) is pathologically identical to MRT of the kidney. CNS MRTs have the clinicopathological behavior of a high-grade intracranial sarcoma, and the children have a very poor prognosis. We report on three cases of primary CNS MRT with a review and summary of the pediatric literature with respect to demographic features and multidisciplinary management. PATIENTS AND METHODS: The 18 cases reviewed had a male to female ratio of 1.0 and an extremely young median age of 32 months. Our three cases of CNS MRT were treated with surgery, chemotherapy, radiotherapy, and triple intrathecal (TIT) chemotherapy similar to the Intergroup Rhabdomyosarcoma Study III guidelines for parameningeal primary tumors with intracranial extension. RESULTS: The three patients described in this report are surviving with no evidence of disease at 5 years, 2 years, and 9 months from diagnosis. Before these three cases, only four of 16 reported patients were known to have survived. One unique case in our report involved disease in the cerebral cortex, sinuses, and orbit with metastases to the subarachnoid space. This metastatic MRT responded to treatment with TIT, multiagent chemotherapy and cranial-spinal radiation after partial resection of only the cortical portion of the MRT. CONCLUSIONS: Disseminated CNS MRTs can be treated using multidisciplinary management with an approach similar to that used to treat rhabdomyosarcoma.

Agreement among and within groups of pathologists in the classification of rhabdomyosarcoma and related childhood sarcomas. Report of an international study of four pathology classifications.

BACKGROUND: An International Pathology study was conducted to measure the agreement demonstrated among and within groups of pathologists involved in the categorization of childhood rhabdomyosarcoma according to four pathology classifications. Data concerning agreement and survival experience according to patho-new subtypes were used as a basis for selection of a proposed new pathologic classification. METHODS: A random sample of 800 eligible patients was chosen from the Intergroup Rhabdomyosarcoma Study II (IRS-II) and was reviewed by pathologists representing eight institutions. A 20% sample of the 800 patients was then reviewed by the pathologists to determine the level of agreement with their original classification. In each instance the patients were classified according to four pathology systems: the conventional system, the International Society for Pediatric Oncology system (SIOP), the National Cancer Institute (NCI) system, and the cytohistologic system. RESULTS: Among the groups of pathologists, the highest measure of agreement was a Kappa value of K = 0.451 for the conventional system, followed by K = 0.406 for the SIOP system, K = 0.384 for the NCI system, and K = 0.328 for the cytohistologic system. For reproducibility within the groups of pathologists, the highest measure of agreement was K = 0.605 for the conventional system, followed by K = 0.579 for the NCI system, K = 0.573 for the SIOP system, and K = 0.508 for the cytohistologic system. CONCLUSIONS: There was a general similarity between the agreement reached within the modified conventional, STOP, and NCI systems, with the modified conventional system having the highest Kappa values, and thus the highest measure of agreement, both among and within the groups of pathologists. Also, the subtypes of the conventional system demonstrated a highly significant relationship to survival time. Hence, based on criteria of reproducibilty and prognostic significance, the proposed classification will essentially be a modification of the conventional system with elements of the SIOP and NCI systems.

Epithelioid sarcoma in childhood: An immunohistochemical, electron microscopic, and clinicopathologic study of 11 cases under 15 years of age and review of the literature.

Epithelioid sarcoma in a rare tumor and most of the cases occur in young adults. It is rare in childhood. We have been able to obtain data and histologic material for 11 patients with this disease. The primary sites were head and neck in three patients, inguinal region in one, and extremities in seven. The age range of the patients was 12 weeks to 13 years. There was a preponderance of males over females with a ratio of 1.75. The tumors presented with a typical nodular necrotizing pattern. In three cases giant osteoclast-like cells were present. The immunohistochemistry and electron microscopy showed features consistent with previous observations on epithelioid sarcomas. In one case islands of small dark cells noted on light microscopy were surrounded by basal lamina on electron microscopy. The cells inside the nests were undifferentiated. Six tumors studied by flow cytometry were in DNA diploid range. On follow-up, five children are alive and well 2 to 7 years after treatment. Three children died of tumor progression with metastases to lymph nodes and lungs. One child had been diagnosed only recently, and in one the disease has run a protractive course with multiple recurrences. The behavior of these epithelioid sarcomas in children is similar to that seen in adults, the prognosis being dependent on radical tumor surgery preventing recurrent disease. Long-term follow-up is necessary because the tumor may recur many years after the primary tumor was removed.

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.

Aicardi syndrome, metastatic angiosarcoma of the leg, and scalp lipoma.

An infant girl with Aicardi syndrome, scalp lipomas, and angiosarcoma of a limb is reported. The cavernous hemangioma of the leg was benign when biopsied at age 5 months but became malignant at 11 months. Angiosarcoma caused multiple distant metastases which were evident at autopsy at age 19 months. This is the first case of Aicardi syndrome associated with lipoma and metastatic angiosarcoma.

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.

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.

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.

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.

Significance of X granules in histiocytosis X: an ultrastructural study.

Histiocytosis X is characterized by the presence of cytoplasmic rod structures called Langerhans' cell granules or X granules (XG). It has been speculated that histiocytosis X is a Langerhans' cell disorder. This ultrastructural study was performed to quantitate the number of XG containing histiocytes in the histiocytosis X lesions. Twenty-four specimens from 22 patients with histiocytosis X were studied: 4 from skin, 5 from lymph node, 11 from bone, 2 from lung, 1 from gingiva, and 1 from cheek. The majority of the histiocytes in histiocytosis X lesions do not contain X granules. The majority of the histiocytes in histiocytosis X lesions do not contain X granules. The percentage of histiocytes with XG in a lesion has no relation to the age of the patient or the organ from which it was obtained, except for skin, where they were quite numerous. The relative percent-age of histiocytes with granules does not correlate significantly with the prognosis of these patients.

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.

The diagnosis and treatment of midline neck masses in children.

Frustration in differentiating before operation among the various causes of midline neck masses stimulated us to review the clinical, operative, and pathologic findings in 176 children hospitalized for a midline cervical lump. The preoperative diagnosis was correct in 61% of these cases, the surgeon's postoperative diagnosis was correct in 83%, and the pathologist's diagnosis was correct in 98%. Only recurrence following prior excision and persistent sinus following drainage of a midline cyst were pathognomonic preoperative indicators of a thyroglossal duct cyst; these findings were present in only 6% of the cases. The age of the child, a history of inflammation or of fluctuation in size, the dimensions of the mass, and the relationship of the mass to the hyoid were useful in differentiating among groups of children with a thyroglossal cyst, an epidermoid cyst, or an enlarged perihyoid lymph node. The duration of the presence of the mass and its movement with swallowing were not helpful. Using the preoperatively recorded historical and physical findings in these children with a known cause for their midline neck mass and applying Bayes' theorem, one can only achieve a correct preoperative diagnosis with an 80% accuracy based on the best available data. Consequently, additional information obtained at surgical exploration is needed to establish a secure diagnosis and to ensure appropriate treatment.