Human neuroblastoma in nude mice.

For establishment of a reproducible model of human neuroblastoma, 2 to 5 million of established neuroblastoma cell lines (SK-N-SH, SK-N-MC) were injected s.c. or i.p. into 20 nu/nu mice of a predominantly Swiss back-ground. Following latency periods of 8 to 21 days, tumors developed at the injection site and grew to 4-ml volumes within 3 weeks. Histologically, the tumors resembled the original metastases from which the tumors were derived; however, the SK-N-SH appeared to have evidence of morphological differentiation. When compared to monolayer culture, the heterotransplanted SK-N-SH tumor had decreased dopamine-beta-hydroxylase activity and elevated cyclic adenosine 3':5'-monophosphate phosphodiesterase activity. Activity of cyclic adenosine 3':5'-monophosphate phosphodiesterase in the transplanted SK-N-MC tumor was not appreciably different from the activity in the cultured cells. Serum dopamine-beta-hydroxylase levels in the mice bearing SK-N-SH tumor increased threefold. The SK-N-MC cultured cells lacked dopamine-beta-hydroxylase and did not alter existing serum levels in the SK-N-MC tumor-bearing mice. 67Ga injected i.v. was found to localize in the tumor after 24 hr. Human neuroblastoma in the nude mouse can be a reproducible and informative model for tumor pharmacology, screening, radionuclides, tumor localization and imaging, and investigating morphological differentiation.

Synchronous neuroblastoma and von Recklinghausen's disease: a review of the literature.

We report an unusual case of progressive disseminated neuroblastoma occurring in a child with a family history and stigmata of von Recklinghausen's disease. A review of the literature confirms the extreme rarity of finding these two neurocristopathies in a single individual and thus undermines the widely held notion of an association--genetic or otherwise--between these two entities. We propose that synchronous neuroblastoma and von Recklinghausen's disease is accounted for by chance alone and therefore represents a randomly occurring phenomenon.

Pediatric desmoid tumor: retrospective analysis of 63 cases.

PURPOSE: This study was conducted to evaluate clinical prognostic factors predictive of the probability of recurrence of desmoid tumor (DT). PATIENTS AND METHODS: Sixty-three patients with histologically confirmed diagnosis of DT were retrospectively studied. Median age at diagnosis was 13 years. Patient distribution by site was as follows: 61% extremities, 18% head and neck, 13% trunk (including 5% intraabdominal), and 8% multicentric lesions. All patients had partial or complete resections; 20 patients also received radiotherapy and/or chemotherapy. RESULTS: At a median follow-up time of 6 years since first treatment, the overall actuarial probability of having one or more recurrences was 75%. Age, sex, site, size, or number of previous recurrences had no significant impact on the likelihood of recurrence. The only factor associated with an increased proportion of recurrence-free patients was a negative margin of resection (70% v 15% with positive margins; P = .006). Of the four patients with more than 3 years follow-up since chemotherapy, two recurred, and of the 11 patients with the same follow-up after radiotherapy, four recurred, including two of five patients who received a dose of 50 Gy or more. No deaths directly related to tumor invasion were observed. CONCLUSION: A surgical approach aiming at clear margins is presently the best treatment option. When this cannot be accomplished without severe disfigurement or function impairment, partial resection is an acceptable alternative, but one associated with a high risk of regrowth. Whether adjuvant strategies should be used in this situation remains to be addressed.

Refinement of clinicopathologic staging for localized soft tissue sarcoma of the extremity: a study of 423 adults.

PURPOSE: The prognostic value of factors used in clinicopathologic staging of localized soft tissue sarcoma (STS) of the extremity were analyzed comprehensively. PATIENTS AND METHODS: Four hundred twenty-three patients with STS that was confined to the extremity were admitted to Memorial Sloan-Kettering Cancer Center from 1968 to 1978. Cox models for the hazards rates of tumor mortality, development of a distant metastasis, strictly local recurrence, and postmetastasis survival were developed. Tests of changes in the prognostic value of the important variables over time were performed, as well as an analysis of the effect of a local recurrence on the hazard rate of distant metastasis. RESULTS: Three unfavorable characteristics contained independent prognostic value for the rates of distant metastasis and tumor mortality: high grade (P less than .00001), deep location (P less than .0002), and size greater than or equal to 5 cm (P less than .007). Their Cox model coefficients did not differ significantly (P greater than or equal to .65); thus, a staging scheme based on the risk of ever developing a distant metastasis would assign equal prognostic weights to grade, depth, and size. The tumor grade effect during the initial 18 months was much larger in magnitude than those for depth and size, and its effect disappeared beyond that time (P = .0003). Thus, a staging scheme based on the risk of early metastatic spread would assign a distinctly larger prognostic weight to grade and lesser but equal weights to depth and size. There was no local recurrence effect on the rate of distant metastasis in the high-risk group (high grade, deep, and greater than or equal to 5 cm; P = .75), but there was a significant association among the remaining groups combined (P = .0039). The magnitude of this association actually increased according to the number of favorable characteristics presented (P = .0024). CONCLUSIONS: The refinement of clinicopathologic staging may depend on the choice of outcome variable: ultimate prognosis versus early metastatic spread. Additionally, the observed local recurrence effect may be explained by a tendency for some patients to acquire one or more unfavorable risk factors at the time of local recurrence.

Role of brachytherapy in the management of desmoid tumors.

From 1977 to 1982, fourteen patients with desmoid tumors underwent surgery and brachytherapy. Surgery ranged from biopsy to complete or partial excision of the tumor. Most of these patients had locally advanced tumor or positive margins. A high recurrence rate is expected in such a group if treated by surgery alone. In twelve out of fourteen patients the treatment was considered curative when all disease sites could be encompassed. In the remaining two patients the treatment was considered palliative because the tumor encroaching on to the spinal cord was left untreated. Ten out of twelve curatively treated patients have remained free of recurrence at a minimum of 2 year follow-up. Five of them were followed from 4-6 years. In the palliatively treated group, one patient is alive with active disease at 18 months. Three patients developed complications with wound healing. This experience suggests that surgery and brachytherapy treatment for desmoid tumor results in higher local control than expected from surgery alone in this selected group of patients.

Aggressive natural killer cell lymphoma/leukemia. A recently recognized clinicopathologic entity.

We report a comprehensive study of a case of aggressive natural killer cell lymphoma/leukemia, which is characterized by young male predominance, rapidly progressive clinical course, and presence of lymphadenopathy, hepatosplenomegaly, and bone marrow involvement. The leukemic phase is frequently preceded by pancytopenia. The diagnostic clues are the detection of cytoplasmic granules in tumor cells on Wright-Giemsa-stained tissue imprints or smears and a selective loss of T-cell antigens. Immunophenotyping is decisive in making the final diagnosis by showing positive natural killer cell markers (CD16, CD56, and/or CD57), CD2, CD11c, and Ia, but negative CD3, T-cell receptor heterodimers, terminal deoxynucleotidyl transferase, and B-cell markers. Genotyping always shows germline configuration in both immunoglobulin and T-cell receptor genes. The unique feature in this case is its presentation as a testicular lymphoma, which has not been previously reported. Polymerase chain reaction was performed in this case but failed to detect human T-cell leukemia virus type I/II provirus. It is important to recognize this new entity as it is a highly aggressive disease with a rapidly progressive clinical course and fails to respond to any chemotherapeutic regimen available.

Prostatic tissue in benign cystic ovarian teratomas.

Benign prostatic tissue was found in three of 25 benign cystic teratomas of the ovary. Our finding may indicate that prostatic tissue in mature ovarian teratomas is more common than currently reflected in literature.

Histiocyte-rich B-cell lymphoma.

This is the second report of histiocyte-rich B-cell lymphoma and the first case analyzed by flow cytometry and cytogenetic study. The immunophenotype determined by flow cytometry was that of a B-cell antigen-positive, surface immunoglobulin-negative B-cell lymphoma with 79% CD11c positive histiocytes. The lymphoid cells were composed of 76% neoplastic B-cells and 24% reactive T-cells. Immunohistochemical staining showed large numbers of histiocytes positive for CD68 and lysozyme in the lymph node and the bone marrow. Neoplastic lymphoid cells were positive for CD20, CD45, CD74 and CDw75. The monoclonality of the tumor cells was established by the evidence of rearrangements of the heavy chain and kappa light chain genes and a complex clonal cytogenetic abnormalities including t(8;14)(q11;q32). The tumor cells were large, pleomorphic lymphoid cells and showed no features resembling those of the L/H cells of Hodgkin's disease as previously reported. The rapidly progressive clinical course in the present case is consistent with the clinical features shown in the original study. The histiocytic component in this tumor is presumably recruited by a lymphokine with the nature of a growth factor from the tumor cells that may also be responsible for the rapid proliferation of the tumor cells and the aggressive clinical course. This entity merits special recognition because it leads to a predictable poor prognosis and because of its potential of being misdiagnosed as true histiocytic lymphoma.

Desmoid tumors of the chest wall. A locally recurrent problem.

Desmoid tumors, in general, are known for their propensity to recur. To evaluate treatment and results, we reviewed the records of 32 patients admitted to our institution with a chest wall desmoid tumor from 1948 to 1988. There were 13 men and 19 women whose ages ranged from 12 to 67 years (median 36 years). Four patients had Gardner's syndrome. Treatment was wide resection. Median follow-up was 110 months. The overall 5-year survival was 93%; 5-year disease-free survival was 71%. The 5-year local recurrence rate was 29%. Since death from disease is uncommon after resection, but local recurrence is common, we recommend aggressive wide resection in patients who have desmoid tumors of the chest wall when seen initially.

Soft tissue sarcomas of the chest wall. Results of surgical resection.

UNLABELLED: Primary soft tissue sarcomas of the chest wall are uncommon, and data concerning treatment and results are sparse. Most studies have categorized these tumors as truncal sarcomas and inferred a poor prognosis. To assess the results of surgical treatment, we reviewed our 40-year experience. METHODS: Records of 189 patients admitted to our institution from 1948 to 1988 were reviewed. Pathologic material was available for review in the 149 cases (79%) that comprise this report. Survival was calculated by the Kaplan-Meier method, with comparisons by log-rank analysis and significance defined as p less than 0.05. RESULTS: Ages ranged from 3 weeks to 86 years (median, 38 years); the ratio of male to female patients was 2:1. The initial complaint was mass or pain in 97% of the cases. Ninety sarcomas (60%) were high grade and 59 (40%) were low grade. Histologic types were as follows: desmoid tumor (n = 32, 21%); liposarcoma (n = 23, 15%); rhabdomyosarcoma (n = 18, 12%); fibrosarcoma (n = 17, 11%); embryonal rhabdomyosarcoma (n = 14, 9%); malignant peripheral nerve tumor (n = 13, 9%); malignant fibrous histiocytoma (n = 11, 7%); spindle cell sarcoma (n = 4, 3%); tenosynovial sarcoma (n = 3, 3%); hemangiopericytoma (n = 3, 3%); alveolar soft part sarcoma (n = 3, 3%); and other types (n = 12, 9%). Resection was the primary treatment in 140 cases (94%). Local recurrence developed in 27%. Metastases occurred in 52 (35%) of the cases (metachronous in 42, synchronous in 10) and were more common in patients with high-grade disease (46/90, 51%) than in those with low-grade disease (6/59, 10%). Overall 5-year survival was 66%. Five-year survival rate for those with high-grade sarcomas (49%) was significantly lower than that for low-grade sarcomas (90%, p less than 0.0001). Tumor size and age of patient were not prognostic. CONCLUSIONS: Survival of patients with primary soft tissue sarcomas of the chest wall after resection is similar to that of patients with sarcomas of the extremities. Resection alone provides acceptable survival (90% at 5 years) for those with low-grade sarcomas, but adjuvant treatment should be considered for those with high-grade sarcomas.

Primary sarcomas of the mediastinum: results of therapy.

UNLABELLED: Primary sarcomas of the mediastinum are rare, and data concerning treatment and results of therapy are sparse. OBJECTIVE: To assess presentation, management, prognostic factors, and survival in mediastinal sarcomas. METHODS: We reviewed our experience with 47 patients with the diagnosis of primary sarcoma of the mediastinum. Data were collected from a computerized institutional database and medical records. Survival was analyzed by Kaplan-Meier method and comparisons of survival by log rank test. RESULTS: The median age of 47 patients with mediastinal sarcoma was 39 years (range 2.5 to 69 years), with a male/female ratio of 1.6. The most common complaints were chest/shoulder pain (38%) and dyspnea (23%). The most common tumor types were malignant peripheral nerve tumor (26%), spindle cell sarcoma (15%), leiomyosarcoma (9%), and liposarcoma (9%). Operation was the primary treatment modality in 72% of cases (n = 34); 22 sarcomas (47%) were completely resected. The overall 5-year survival was 32%. High-grade lesions had a significantly decreased survival (5-year survival = 27%) compared with low-grade tumors (5-year survival = 66%) (p = 0.05). The overwhelming factor determining survival was the ability to completely resect the tumors (5-year survival 49% for complete resection; 3-year survival 18% for incomplete or no resection) (p = 0.0016). Despite complete resection, local recurrence occurred in 64% of cases. CONCLUSION: Because the overall survival for patients with mediastinal sarcomas is 32% and the local recurrence is 64% for tumors completely resected, aggressive adjuvant therapy should continue to be systematically explored.

Percutaneous aspiration biopsy of lymph nodes.

During a period of five years, 361 patients each had cytologic examination of a specimen aspirated by percutaneous needle biopsy from a superficial lymph node. Fifty-five aspirates were considered unsatisfactory owing to scanty cellularity, and 22 were excluded because of lack of adequate follow-up. Of the remaining 284 aspirates, 81% were positive for malignant cells; 19% were considered negative. There were no cases with false-positive diagnoses. However, of 52 negative aspirates, 31 revealed tumor on subsequent excisional biopsy. Seventy-two percent of patients were admitted with prior history of malignancy. For both males and females, an apparent correlation was found between regional distribution of positive lymph nodes and the histologic types of primary tumors. Eighty-two percent of the positive cervical nodes in males and 56% in females were associated with epidermoid carcinoma. Most of the positive supraclavicular and axillary lymph nodes occurred in females and were associated with mammary carcinoma. Diagnosis of malignant neoplasms is feasible, in most instances, from nodal aspirates, but specific diagnosis of the histologic type of the tumor, e.g., malignant lymphoma, should be rendered only when the cytologic findings are supported by appropriate clinical and laboratory findings. In case of doubt, or if the aspirate contains many polymorphonuclear leukocytes, necrotic debris, or bizarre epithelioid cells, granulomatous lymphadenitis should be suspected and the diagnosis should be deferred until formal tissue biopsy can be obtained.

Spinal fluid cytology during chemotherapy of leukemia of the central nervous system in children.

During a two-year period 170 children were treated for leukemia. Forty-seven per cent had clinical and cytologic evidence of central nervous system involvement. Of these, 38 patients had repeated cytologic examinations of the spinal fluid and were suitable for a study of changes that occurred during the course of their disease and treatment. A total of 112 cytologyc specimens from the 38 patients over a period of 8 to 60 months was reviewed. There was accurate correlation between cytologic evidence of leukemia in the spinal fluid, clinical signs and symptoms of central nervous system disease, and autopsy evidence of meningeal leukemia, though the number of cells present did not predict the severity of clinical disease or extent of meningeal infiltrate. Almost every patient with leukemic cells in the spinal fluid had a corresponding leukemia infiltrate in the bone marrow, but not in peripheral blood. The differential diagnosis of leukemia in spinal fluid cytology is discussed and the clinical response to intrathecal chemotherapy correlated with cytologic findings. Serial cytologic observations during treatment, and the phenomenon of autonomous CNS leukemia, are discussed in terms of cell cycle physiology and chemotherapy. The results stress the usefulness of spinal fluid cytology as a screening procedure in asymptomatic patients with leukemia and are of interest in regard to the pathophysiology of leukemia of the central nervous system.

Prognostic factors in primary retroperitoneal soft-tissue sarcomas.

We analyzed independent treatment variables (age, sex, signs and symptoms, site, size, histopathologic findings, grade, and clinical presentation) and treatment-dependent variables (resectability, type of operation, surgical margins, surgical boundaries, microscopic margins, adjuvant radiotherapy, and adjuvant chemotherapy) in 80 patients with primary retroperitoneal soft-tissue sarcomas admitted from 1982 through 1988. Both univariate and multivariate analysis of survival and disease-free survival were performed. The major factor in survival outcome was the ability to completely resect the lesion. When the 62 patients who underwent complete resection were examined, the only independent prognostic factor for both survival and disease-free survival was grade. We conclude that completeness of resection and grade of the lesion are primary determinants of survival. Once all tumor is macroscopically removed, no advantage could be demonstrated by more extensive surgical resection or current adjuvant therapy.

Malignant soft-tissue tumors of the anterior abdominal wall.

A clinicopathologic study was made of 32 soft-tissue sarcomas of the anterior abdominal wall (ten desmoid tumors and 22 fully malignant sarcomas). Direct invasion of the costal margin or the iliac crest was observed in both types, whereas transperitoneal invasion and metastasis developed characteristically with fully malignant sarcomas. Wide monobloc resection of the abdominal wall, including, where necessary, resection of adjacent bony parts and reconstruction with a prosthetic mesh, satisfactorily controlled local disease in nine of ten patients with desmoid tumor, and in three of four patients with primary operable, fully malignant sarcoma. Adjunctive therapy with radiation and chemotherapy may improve the outcome in patients with recurrent or high-grade sarcomas, but adequate monobloc resection of the primary tumor remains the most important therapeutic objective.

Vascular soft-tissue sarcomas. An analysis of tumor-related mortality.

Between 1982 and 1990, 69 adult patients were admitted to Memorial Sloan-Kettering Cancer Center with a diagnosis of angiosarcoma, lymphangiosarcoma, or malignant hemangiopericytoma. The existing literature regarding sarcomas focuses on individual histologic conditions or site-specific activity and includes pediatric patients, which makes estimates of survival difficult. We describe the clinical course of all vascular sarcomas, the survival without distant recurrence of patients with vascular sarcomas, and the overall survival of patients with vascular sarcomas. Using Cox's stepwise regression model, histologic characteristics of the tumors, tumor grade, tumor size, and other factors were assessed to determine their prognostic significance. Noncurative treatment and the presence of metastases were the only two factors influencing survival. Tumor grade approached significance. Disease recurrence was common among curatively treated patients (37% of such patients), and more than half of these recurrences involved distant sites. The survival of these patients depends on complete surgical resection and is independent of individual histologic characteristics of the tumor.

Multifactorial analysis of long-term follow-up (more than 5 years) of primary extremity sarcoma.

BACKGROUND: The majority of survival studies in patients with extremity soft tissue sarcoma have focused on early recurrence and mortality. There are few data addressing long-term follow-up and survival. OBJECTIVE: To analyze survival and recurrence in patients with extremity soft tissue sarcoma who survive for more than 5 years. METHODS: Patients who underwent treatment for primary tumors (July 1982 to July 1994) and were followed up for more than 5 years were the subject of study. Disease-specific and disease-free survival were determined actuarially. Significance was evaluated using log-rank testing for univariate analysis and Cox model stepwise regression for multivariate analysis. RESULTS: A total of 495 patients with primary extremity tumors were treated before July 1989 and eligible for 5-year follow-up. Of these, 282 have been followed up for more than 5 years (median follow-up, 84.4 months). Actuarial disease-specific survival of patients who survive for longer than 5 years was 79%+/-7% (+/-SEM) at 10 years, and of those who were metastasis free at 5 years was 91%+/-4% at 10 years. On univariate analysis, post-5-year disease-specific survival was influenced by positive microscopic margin and initial tumor size of 5 cm or greater. On multivariate analysis, post-5-year disease-specific survival was influenced only by positive margins. CONCLUSIONS: Based on these analyses, 21% of patients with primary extremity sarcoma who survive for 5 years will die of disease within 5 years. Even of those who are metastasis free at 5 years, 9% will die of disease within 5 years. In contrast to early mortality, tumor grade has no influence on post-5-year prognosis. Patients with positive microscopic margins are at risk for post-5-year disease-specific mortality and therefore require long-term follow-up and consideration for investigational therapy.

Primary colorectal sarcoma. A retrospective review and prognostic factor study of 50 consecutive patients.

Fifty patients were admitted to Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, NY, with primary colorectal sarcoma between 1948 and 1987. Thirty-one patients (62%) presented with a high-grade tumor, 37 patients (74%) with a tumor larger than 5 cm, and 12 patients (24%) with metastasis. The median survival of the whole group was 33 months, and the median survival of patients who underwent curative operation was 174 months. Nineteen of 32 patients who underwent curative operation were observed to develop distant metastasis after 3 to 209 months. The dominant sites of metastatic disease were the liver and peritoneal cavity. In a multivariable analysis, noncurative treatment and high-grade tumor were the only prognostic factors unfavorably affecting tumor-related mortality. If the type of treatment received was not considered, presentation with metastatic disease and a high-grade tumor were the two unfavorable characteristics that had independent prognostic value. Patients with a tumor that was larger than 5 cm or that was located in the colon had a greater likelihood of having a palliative procedure or high-grade tumor.

Local recurrence in adult soft-tissue sarcoma. A randomized trial of brachytherapy.

We conducted a prospective randomized study of the benefit of adjuvant radiation therapy delivered by the brachytherapy technique in 117 adult patients who had soft-tissue sarcoma that was on an extremity or superficially localized to the trunk. A significant decrease in local recurrence was demonstrated in the patients receiving brachytherapy. The benefit did not appear to be due to any maldistribution in the known prognostic factors of size, site, depth, presentation with recurrence, or histologic grade. The decrease in local recurrence appears to be due to the decreased local recurrence in high-grade sarcomas. Survival differences were not identified, and accrual and follow-up were continued.

The desmoid tumor. Not a benign disease.

The necessity of aggressive therapy for desmoid tumors has not been clearly established. To evaluate the therapeutic value of adequate resection and radiation therapy, we conducted a retrospective study of 138 patients treated from 1965 through 1984. Univariate analysis revealed five factors predictive of local failure: (1) age between 18 and 30 years, (2) presentation with recurrent disease, (3) partial or limited margin excision, (4) tumor at or close to the microscopic margin of resection, and (5) radiation therapy not administered for gross residual disease. Multivariate analysis identified two of these factors as having independent predictive value for recurrence: (1) presentation with recurrent disease and (2) less-than-adequate margins of resection. The five-year survival probability was 92%, but 11 of the 138 patients died as a consequence of locally uncontrolled tumor. These findings confirm that desmoid tumors are malignant soft-tissue neoplasms that warrant aggressive therapy.