Outcome of flat bone sarcomas (other than Ewing's) in children and adolescents: a study of 25 cases

We analysed the clinical features and outcome of young patients with non-Ewing's flat bone sarcoma treated during the era of contemporary chemotherapy. The characteristics and outcome of 25 patients (15 males and 10 females) with primary or radiation-related flat bone sarcoma treated in the Pediatrics Department at the Institut Gustave Roussy from 1981 to 1999 were reviewed. In all, 20 patients had osteosarcoma, four chondrosarcoma and one malignant fibrous histiocytoma. The age at diagnosis ranged from 2 to 23 years (median, 15 years). Nine tumours were located in the craniofacial bones, 11 in the pelvis and five in flat bones at other sites. Four patients had metastatic disease at diagnosis. Radiation-associated flat bone osteosarcoma was diagnosed in 10 out of 25 cases. The projected overall survival and event-free survival (EFS) rates at 5 years were 45.1 and 34.3% for all the 25 patients. The EFS rate of patients with second bone sarcoma was similar to that of patients with de novo flat bone sarcoma (P=0.1). The aim of treatment was curative for 24 patients, 23 of whom were treated with intensive chemotherapy regimens and 19 with surgery. Significant adverse prognostic factors on survival included incomplete surgical resection (P=0.001) and use of regimens without pre- and postoperative chemotherapy (P=0.007). Nine of the 25 patients were treated with pre- and postoperative chemotherapy and complete surgical resection. Among them, eight are alive with no disease. Radical surgical resection is the overriding prognostic factor for flat bone sarcomas in young patients. Nevertheless, our results suggest a more favourable outcome since the advent of intensive chemotherapy.     

Osteosarcomas of flat bones in adolescents and adults

BACKGROUND: Osteosarcomas typically are long bone tumors and rarely affect the flat bones of the axial or appendicular skeleton. METHODS: The authors examined cases of high grade osteosarcoma of flat bones diagnosed at La Timone Adults University Hospital during a 16-year period. RESULTS: Sixteen patients with flat bone osteosarcomas were treated between 1980-1997. The median age of the patients was 25 years, with a male-to-female ratio of 14:2. Common presenting symptoms were swelling, pain, or both. Primary therapy included resection (n = 11 patients: alone in 8 patients and with radiation therapy in 3 patients), radiation therapy (n = 2 patients), or no local treatment (n = 3 patients). All patients received polychemotherapy, 7 preoperatively and postoperatively and 9 in the adjuvant setting. The overall 5-year survival rate was 47.7%; the overall median survival was 39 months (range, 4-211 months). The adequate local control rate was 68.7%. The local recurrence rate in patients who benefited from local treatment was 54%. Significant adverse prognostic factors on survival included the presence of synchronous metastases (three patients), metastases at any time during the course of the disease (eight patients), and inadequate local control (five patients). The overriding predictor of survival appeared to be the presence of metastases. Local recurrence appeared to have no influence on survival. No patient with metastases was alive at 3 years, whereas patients without recurrence or with local recurrence alone had a 5-year survival rate of 100%. Because the majority of patients with flat bone osteosarcomas ultimately die of metastatic disease, intensive systematic polychemotherapy should be an important component of treating these tumors. CONCLUSIONS: Based on the very encouraging results observed in the treatment of long bone osteosarcomas, the therapy for flat bone osteosarcomas should combine radical surgery with preoperative and postoperative adjuvant chemotherapy.     

Ewing's sarcoma in bones of the hands and feet: a clinicopathologic study and review of the literature

Review of current data from the Intergroup Ewing's Sarcoma Study (IESS) shows that Ewing's sarcoma (ES) is rare in bones of the hands and feet. Only 12 of 377 evaluable patients in the first two IESS studies had a primary tumor in these small, distal bones. The age distribution was typical for that seen in patients with ES at other sites. Males were affected twice as often as females, and tumors in the bones of the feet were much more common than those in the hands. All signs and symptoms were local in distribution. As in other sites, the dominant histologic pattern was categorized as diffuse. With the exception of those patients with lesions in the calcaneus, the prognosis for disease-free survival was excellent. A literature review of cases of ES reported in bones of the hands and feet showed generally comparable results.     

Adamantinoma of long bones. A clinicopathologic study of 85 cases

A study of 85 adamantinomas of long bones revealed that 70 were in the tibia (11 of which also involved the fibula), six were in the femur, three were in the ulna, two were in the humerus, two were in the fibula, one was in the radius, and one arose in the soft tissue anterior to the tibia. Most patients presented with pain and swelling and were aged 10 to 30 years. The histologic appearance was that of epithelial islands in a fibrous stroma, usually with a prominent vascular pattern and a transition between the two. Twenty-six (31%) patients had recurrent local disease, 13 (15%) developed lung metastasis, and six (7%) had lymph node metastasis. Nine patients with lung metastasis had preceding recurrent local disease. Risk factors for recurrent or metastatic disease included male sex, pain, symptoms of less than 5 years' duration, and initial treatment by biopsy, curettage, excision, or resection. The only histologic feature associated with an increased recurrence rate was lack of squamous differentiation. Eleven patients died of their disease, and seven are alive with metastatic disease. Forty-one patients were still alive without disease 1 month to 47 years after treatment. Our results indicate that amputation or, when technically feasible, wide en bloc resection is the treatment of choice. All patients require long-term follow-up for evidence of local recurrence or lung metastasis.     

Diencephalic gliomas of children. A clinicopathologic study

The authors reviewed the clinical information and pathology specimens from 29 children with diencephalic gliomas to determine whether any clinical or histopathologic feature correlated with prognosis. The median survival time for the entire group was 3.96 years. No symptom or sign at the time of diagnosis correlated with outcome. The tumors consisted of 25 astrocytomas or mixed gliomas and 4 malignant astrocytomas-mixed gliomas. Median survival time of the 25 children with astrocytomas-mixed gliomas was 4.8 years, compared with 0.5 years for the 4 children with malignant tumors. The tumor histology was relatively uniform: most tumors were moderately cellular astrocytomas with pleomorphism and hyperchromatism but without mitoses, hemorrhage, or necrosis. High cell density and the presence of mitoses were the two histologic features significantly associated with poor prognosis; no child with mitosis survived longer than 14 months.     

Osteogenic sarcoma of bones and soft tissues in older persons. A clinicopathologic analysis of 117 patients older than 60 years

Since 1930, 117 patients with well-documented osteogenic sarcoma of the skeleton and the soft tissues occurring in patients older than 60 years have been diagnosed and treated at Memorial Hospital for Cancer and Allied Diseases. This number represents approximately 10% of all osteogenic sarcomas treated at this Medical Center. Slightly more men than women (68 versus 49, respectively) were affected, with a mean and a median age of 68 and 66 years, respectively, ranging from 60 to 86 years of age. One hundred one lesions occurred in the skeleton and 16 in extraosseous sites. In contrast to osteogenic sarcoma in children and adolescents, where more than half of the tumors arise in the fastest-growing bony sites around the knee, this region was involved in only 14.5% of the older patients. In this latter age group, the axial skeleton was the most commonly affected (27%), in addition to the craniofacial bones (13%) and extraskeletal sites (11%). Contrary to expectations, the lytic destructive skeletal lesions were three times more common than any other radiographic presentation, with the fibrous (38%), the osteoblastic (25%), and the cartilaginous (17%) sarcoma variants predominating over all others on histologic examination. Whereas 97% of osteogenic sarcomas occurring in patients younger than 21 years arise anew, without any pre-existent osseous disease, in this study's older population, sarcomas were more frequently (56%) secondary to other bony conditions, such as Paget's disease, or followed irradiation. Five-year survival estimates were strongly dependent on whether the patients had primary de novo osteogenic sarcomas (37%) or whether the sarcomas arose secondary to other skeletal conditions (7.5%). There are no significant survival differences between patients treated before or after 1974, when adjuvant and neoadjuvant chemotherapy started to make its positive impact in the treatment of osteogenic sarcoma in children and adolescents.     

Prognostic value of clinicopathologic characteristics including neuroectodermal differentiation in osseous Ewing's sarcoma family of tumors in children.

AIMS AND BACKGROUND: The aim of the present study was to determine the relationship between clinico-pathologic parameters, including neuroectodermal differentiation, and their impact on survival in a series of pediatric patients with osseous tumors of the Ewing's sarcoma family admitted to the Pediatric Department of the Istituto Nazionale Tumori of Milan. METHODS: Seventy-three patients were enrolled. The variables analyzed were sex, age, site of primary tumor, serum lactate dehydrogenase (LDH) level at diagnosis, involvement of periosseous soft tissues by primary tumor, presence of metastatic disease, status of disease after the treatment plan, as well as the presence of mitoses, morphologic and immunocytochemical neural markers, and neuroendocrine markers in the primary tumor. RESULTS: Neural and neuroendocrine markers were not significantly associated with any of the other parameters. In the univariate analysis, significant risk factors related to unfavorable outcome were elevated LDH, metastatic disease, lack of complete remission after treatment, presence of mitoses and of morphological neural markers; immunocytochemical neural and neuroendocrine markers lacked prognostic value. In the multivariate analysis, only LDH levels and the status of disease following the treatment were retained. CONCLUSIONS: LDH level at diagnosis might be a useful marker to identify different risk levels; neuroectodermal differentiation might have no clear-cut impact on the clinical management of osseous Ewing's sarcoma family of tumors.     

t(11;22) and other chromosomal rearrangements in Ewing's sarcoma

Abnormal karyotypes from 13 human cases of Ewing's sarcoma are reported in this paper. The t(11;22) was seen in 9 cases, with 2 additional cases containing only a del(22). Other abnormalities included trisomy of 1q, translocations to 19p13, deletions of 3p and 6q, and homogeneously staining regions.     

Pulmonary lymphomas and other pulmonary lymphoid lesions. A clinicopathologic and immunologic study of 64 patients

Sixty-four patients with lymphoid lesions involving the lung were separated into three groups. In 32 patients, the predominant lymphoid cell population consisted of small, mature-appearing round lymphocytes with or without plasmacytoid features. This group, designated small lymphocytic proliferation (SLP), represents a heterogeneous group of pulmonary lymphocytic lesions including small lymphocytic lymphoma, lymphocytic interstitial pneumonia, and lymphoid hyperplasia (pseudolymphoma). Thirteen SLP patients were identified as having small lymphocytic lymphoma on the basis of monoclonality, progressive disease in other sites, or both. This group was morphologically identical to the remainder of the SLP patients, except for a higher incidence of plasmacytoid features (P = 0.003) and a greater degree of mast cell infiltration (P less than 0.05). Four of these 13 patients subsequently developed an aggressive large cell lymphoma resulting in death in three patients. The median survival for all of the SLP patients has not yet been reached. Patients in whom a monoclonal cell population could be established showed a slightly worse prognosis of borderline statistical significance (P = 0.09); however, the presence of a serum monoclonal gammopathy conveyed a significantly worse prognosis (P = 0.003). The remaining two groups of patients had various forms of malignant lymphoma other than the small lymphocytic type. One group of 12 patients, designated as having presumed primary lymphoma limited to one or both lungs (PL), had a prolonged course with a median survival of 117 months. The remaining 20 patients had disseminated lymphoma also involving lung (DL); DL patients had a shorter median survival of 33 months.     

Renal cell carcinoma in children: a clinicopathologic study.

PURPOSE: To identify the prognostic factors, treatment, and outcome of children affected by renal cell carcinoma (RCC). PATIENTS AND METHODS: The series included 41 patients (18 males and 23 females) with a median age of 124 months observed at the 11 Italian Association for Pediatric Hematology and Oncology centers from January 1973 to January 2001. Clinical data, surgical notes, pathologic findings, and summaries of therapy were taken from the charts. RESULTS: Seven (17%) of the 41 patients had a papillary histology, and 34 (82.4%) had nonpapillary histology. Eighteen patients (43.9%) had stage I, one patient (2.4%) had stage II, two patients (4.8%) had stage IIIA, 10 patients (24.3%) had stage IIIB, and nine patients (21.9%) had stage IV disease. One patient had a bilateral involvement at diagnosis. Seven patients experienced disease recurrence. Lung and liver were the most common distant lesions and usually were fatal. In this study, the major factor influencing the prognosis was the stage. Event-free survival at 20 years was 53.5% for all patients. Overall survival at 20 years was 54.9% for all patients. CONCLUSION: RCC is a rare disease in children and adolescents. This neoplasm has a different clinical presentation in children compared with adults but the same outcome. In our experience, patients with localized disease could be cured by nephrectomy alone. Prospective studies in a larger number of patients are needed to confirm radiation therapy and biologic response modifiers as effective adjunct therapy in RCC stage III. The alternative therapy seems warranted in patients with advanced disease.     

Sarcomas and sarcomatoid neoplasms of the major salivary gland regions. A clinicopathologic and immunohistochemical study of 67 cases and review of the literature

Sixty-seven cases of sarcomas and sarcomatoid neoplasms of the major salivary gland regions were studied in order to determine the clinical and histomorphologic features and biologic behavior. Fifty-seven of these proved to be sarcomas and the two most common types were malignant schwannoma (11) and fibrosarcoma (9). Nine sarcomas could not be subclassified morphologically. Ten cases, originally believed to be sarcomas, proved by means of immunohistochemistry to be either carcinomas (five cases) or melanomas (five cases). Fifty-nine of the 67 cases occurred in the parotid gland regions, and the remaining eight occurred in the submandibular regions. Twenty of the 67 cases were thought to arise from within the gland, nine from paraglandular tissues, and insufficient data was present to anatomically categorize the other 38 cases. The mean age of occurrence was 42 years for men and 38 years for women. A swelling was the presenting symptom in 64 cases, with a mean duration of 4.3 months. Pain, tenderness, or paralysis were noted in 17 cases, but the swelling was painless in seven cases. Follow-up data of 42 sarcoma patients revealed that 17 experienced recurrences, 16 developed metastases, and 15 died of disease. These rates were lowest among patients with tumors arising from within the gland (Group I) and highest among those patients with tumors of paraglandular origin (Group III). Mean survival time for those dying of disease was 2.4 years, and a 5-year survival time appeared to be a significant indicator of cure. The most successful therapy was either parotidectomy (superficial or total) or a combination of surgery and radiation. The morphologic and the immunohistochemical evidence suggest that the majority of the tumors represent true sarcomas that may arise from undifferentiated pluripotential cells, but that the remainder (15%) represent epithelial malignancies.     

Ovarian Sertoli-Leydig cell tumor (androblastoma) with retiform pattern. A clinicopathologic study

The clinicopathologic findings in nine patients with ovarian Sertoli-Leydig cell tumor with retiform pattern are described. The patients ranged in age from 11 months to 23 years; and seven patients were 12 years of age or younger. The most frequent presenting sign was the finding of an abdominal mass. This was associated with pain in five patients. In three patients the pain was severe due to torsion, causing an acute abdominal emergency. Slight virilization was observed in one patient only. Two patients had elevated serum alphafetoprotein (AFP), which correlated well with disease activity. The remaining patients had normal serum AFP. All the tumors were unilateral. At laparotomy the tumor was intact in six patients and ruptured in three. The tumors ranged from 8 to 22 cm, were round or oval, and cystic or solid and cystic. Eight tumors were in FIGO Stage I, and one was associated with abdominal metastases and was Stage III. Histologically, the retiform component varied from moderate to predominant in eight of the nine cases. In two tumors a heterologous component composed of striated muscle was also present. Three patients developed metastases. Two of the patients died 11 months and 2 years after diagnosis and the third patient was lost to follow-up with evidence of disease 2 years after diagnosis. The remaining six patients were well and disease-free for periods of 8 months to 6 years. The majority of these tumors were misinterpreted as serous papillary cystadenocarcinoma or endodermal sinus tumor, which are more malignant neoplasms requiring different therapy. This further underlines the importance of recognizing this histopathologic entity.     

Rhabdomyosarcoma in children and adolescents. A review

Children and adolescents with RMS presently have an overall survival of 60 to 65 per cent when treated with multimodality therapy. Those individuals with favorable histologic features and either complete resection or microscopic residual have an 80 to 85 per cent probability of long-term survival. These accomplishments by the IRS committee of the Children's Cancer Study Group and the Pediatric Oncology Group have been extended to thousands of patients. Other investigators in the United States, Great Britain, and Europe, working both in collaboration and independently of the IRS, have been responsible for innovative therapies, which should further reduce the mortality and morbidity of this common soft tissue sarcoma. Increasing emphasis is being placed on the tumor biology, molecular genetics, and epidemiology of RMS, as well as on the quality of life in survivors. At the fifteenth anniversary of its inception, the IRS has fulfilled the expectations of its founders as a model for intergroup collaborative research. Credit for these accomplishments can only go to the hundreds of investigators and their patients who have participated in these studies.     

Familial aggregation of nasopharyngeal carcinoma and other malignancies. A clinicopathologic description.

Nasopharyngeal carcinoma (NPC) occurred in five members in three generations of a white American family of Scandinavian descent. Six other family members had malignancies including malignant melanoma, malignant lymphoma, squamous cell carcinoma of the tongue, adenocarcinoma of the colon, and asynchronous bilateral in situ and invasive ductal carcinomas of the breast. There was also a history of autoimmune disorders and exposure to smoke, fumes, and chemicals in some family members. Regression analysis revealed a significant covariate risk for exposure to smoking, alcohol ingestion, dust, salted or spicy foods, and poorly ventilated conditions. According to segregation analysis, the susceptibility to nasopharyngeal carcinoma and other malignancies in this family was transmitted as an autosomal codominant characteristic. A specific histocompatibility antigen (HLA) haplotype of A1-B37-DR6 was associated with a predisposition for NPC, but no linkage was identified. Laboratory studies in selected family members did not reveal significantly elevated levels of Epstein-Barr virus antibodies or serum carcinoembryonic antigen. No specific karyotypic abnormalities were identified with peripheral blood chromosome analysis. This family was an example of apparent autosomal codominant susceptibility to NPC and other malignancies. The relationship of malignancy to the HLA haplotype of A1-B37-DR6, autoimmune disorders, and cytogenetic abnormalities was intriguing but not defined clearly.     

Extraosseous Ewing's sarcoma. A study of 42 cases

Fifty patients at the Mayo Clinic (Rochester, MN) from 1935 to 1985 met the histologic criteria for extraosseous Ewing's sarcoma. Forty-two had soft tissue primaries without bony involvement and formed the basis for this retrospective study of the clinical behavior and management of extraosseous Ewing's sarcoma. There were 19 male and 23 female patients (mean age, 22 years). Metastases were documented in 30 of the patients, six at the time of presentation and 24 occurring up to 11 years later, most commonly to lungs or bone. Three patients were lost to follow-up. Sixteen of 35 patients (46%) had local recurrence. Overall survival was 15 of 39 (38.5%) at 5 years. Decreased survival was noted with pelvic tumors, incomplete resections, and presence of metastatic disease, whereas increased survival was associated with wide surgical resection with negative microscopic margins, adjuvant local radiation therapy, and presentation since 1970 (48% 5-year survival compared with 28% before 1970).     

Primary Ewing's sarcoma of the ribs. A report from the intergroup Ewing's sarcoma study

Thirty-six patients with primary Ewing's sarcoma of the ribs have been reviewed. Of these, 21 had clinically localized disease at diagnosis and were entered on protocol IESS 7299, eight had regional and seven metastatic disease at diagnosis and were entered on protocol 7450. The 21 with localized disease were treated with surgical excision or biopsy, followed by local radiotherapy (in all but one patient) and randomization to one of three chemotherapy regimens. Eleven patients (52%) remain disease-free for periods ranging from 18 to 64 months, respectively. Seven of eight patients who underwent complete surgical excision of the primary lesion remain disease-free, compared with four of 12 (excluding one patient who died disease-free) who remain disease-free after partial excision or biopsy. However, analysis of size of tumor at diagnosis reveals that smaller primary tumors have a better prognosis irrespective of extent of surgery. Protocol IESS 7450, consisted of radiotherapy to all areas of known disease and four drug chemotherapy. Four (50%) with regional disease but none with metastatic disease have remained alive and continuously disease-free. It is concluded that an aggressive approach to Ewing's sarcoma of the ribs is justified by the results, as even regional disease may be curable. The apparent prognostic advantage for those patients undergoing surgical excision may be explained by patient selection.     

A biochemical and immunohistological study of collagen synthesis in Ewing's tumour.

The synthesis and localization of collagen have been studied on material from a total of 16 primary Ewing''s tumours. The predominant collagen extracted from the tissues and synthesized in short-term cultures was type I. The proportion of type III collagen was relatively small and variable (0-8%) in the direct tumour extracts, but a higher proportion (29-38% of the total collagens) was synthesized in culture. Immunofluorescence studies showed that positive staining for all types of collagen tested (types I, III, IV and V) was restricted to stroma; there was no evidence of collagen either within the tumour cells or in their pericellular matrix, a finding endorsed by negative staining for reticulin in the same areas. The absence of any evidence for type IV or V collagen synthesis by Ewing''s cells argues against an endothelial origin for the tumour, and indicates that collagen analysis is unlikely to be of value in the diagnosis of this particular sarcoma.     

Ackerman's tumor (verrucous carcinoma) of the larynx. A clinicopathologic study of 77 cases

A series of 77 cases of verrucous carcinoma of the larynx is presented. The tumor is relatively rare and the present series has been selected from 2,398 primary and recurrent malignant neoplasms of the larynx and hypopharynx evaluated at the Department of Otolaryngology of Padua University during the period from January 1966 to December 1978. The median age of patients was 58 years. The tumor appears to be exophytic, broadly implanted and fungating in aspect, with papillary fronds and a locally invasive character. It is composed of highly differentiated epithelial squamous cells covered by a thick keratinized layer arranged in deeply invaginated folds. Cellular response in tumor stroma is marked, and the neoplasm has a low-grade malignancy. Close cooperation between the pathologist and the clinician is needed in order to establish the nature of the lesion, which looks clinically malignant but may appear histologically benign. Benign responses such as hyperkeratosis, acanthosis, or the presence of a benign papillomatous area necessitate further investigation with another biopsy examination from deeper layers. The elective treatment is surgery, as irradiation may cause anaplastic transformation with metastatic spread. Neck dissection is not indicated as this laryngeal tumor has so far never metastasized to cervical lymph nodes or to other organs.