Joseph M. Corson

Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group.

One‐hundred‐ninety‐four eligible and evaluable patients with histologically confirmed locally unresectable adenocarcinoma of the pancreas were randomly assigned to therapy with high‐dose (6000 rads) radiation therapy alone, to moderate‐dose (4000 rads) radiation + 5‐fluorouracil (5‐FU), and to high‐dose radiation plus 5‐FU. Median survival with radiation alone was only 51/2 months from date of diagnosis. Both 5‐FU‐containing treatment regimens produced a highly significant survival improvement when compared with radiation alone. Forty percent of patients treated with the combined regimens were still living at one year compared with 10% of patients treated with radiation only. Survival differences between 4000 rads plus 5‐FU and 6000 rads plus 5‐FU were not significant with an overall median survival of ten months. Significant prognostic variables, in addition to treatment, were pretreatment performance status and pretreatment CEA level.

Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma : results in 183 patients

OBJECTIVES Our aim was to identify prognostic variables for long-term postoperative survival in trimodality management of malignant pleural mesothelioma. METHODS From 1980 to 1997, 183 patients underwent extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy. RESULTS Forty-three women and 140 men (age range 31-76 years) had a median follow-up of 13 months. The perioperative mortality rate was 3.8% (7 deaths) and the morbidity, 50%. Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell type (52% 2-year survival, 21% 5-year survival, 26-month median survival; P =.0001), negative resection margins (44% at 2 years, 25% at 5 years, median 23 months; P =.02), and extrapleural nodes without metastases (42% at 2 years, 17% at 5 years, median 21 months; P =.004). Using the Cox proportional hazards, the relative risk of death was calculated for nonepithelial cell type (OR 3.0, CI 2.0-4.5; P <.0001), positive resection margins (OR 1.7, CI 1.2-2.6; P =.0082), and metastatic extrapleural nodes (OR 2.0, CI 1.3-3.2; P =.0026). Thirty-one patients with 3 positive variables had the best survival (68% 2-year survival, 46% 5-year survival, median 51 months; P =.013). A previously published staging system using these variables stratified survival (P <.05). CONCLUSIONS (1) Multimodality therapy including extrapleural pneumonectomy is feasible in selected patients with malignant pleural mesotheliomas, (2) pre-resectional evaluation of extrapleural nodes may select patients for radical therapy, (3) microscopic resection margins affect long-term survival, highlighting the need for further investigation of locoregional control, and (4) patients with epithelial, margin-negative, extrapleural node-negative resection had extended survival.

Diagnostic relevance of clonal cytogenetic aberrations in malignant soft tissue tumors

BACKGROUND Malignant soft-tissue tumors often present substantial diagnostic challenges. Chromosome aberrations that might be diagnostic have been identified in some types of soft-tissue tumors, but the overall frequency and diagnostic relevance of these aberrations have not been established. METHODS We attempted to determine the karyotypes of a series of 62 consecutive, unselected malignant spindle-cell or small round-cell soft-tissue tumors (from 46 adults and 16 children) after direct harvesting of cells or short-term culture. All tumors were examined independently by immunohistochemical staining in addition to routine light-microscopical evaluation, and all but two tumors were examined by electron microscopy. RESULTS Metaphases were obtained from 61 of the 62 tumors, and clonal chromosome aberrations were identified in 55 (89 percent). In the six tumors that yielded metaphases but lacked apparent clonal aberrations, the normal metaphases were found to originate from non-neoplastic stromal elements within the tumor specimens. Thus, all tumors in which karyotyping was successful contained clonal chromosome aberrations. Forty of 62 tumors (65 percent) contained clonal chromosome aberrations that either suggested or confirmed a specific diagnosis; in 15 of these tumors (24 percent of all tumors), the aberrations were important in establishing the final diagnosis. Cytogenetic analyses were particularly informative about small round-cell tumors from children: 8 of 14 round-cell tumors contained diagnostically important chromosome aberrations. Using the combined approaches of light and electron microscopy, immunohistochemistry, and cytogenetics, we established an unambiguous diagnosis for 60 of 62 tumors. CONCLUSIONS Cytogenetic analyses reveal clonal chromosome aberrations in virtually all malignant soft-tissue tumors. These clonal chromosome aberrations, particularly in small round-cell tumors in children, often have diagnostic relevance.

Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women's Hospital experience over two decades, 1965-1985.

All mesothelioma patients identified by a computer search of pathologic diagnoses at the Dana-Farber Cancer Institute (DFCI) between 1965 and 1985 were the subjects of this analysis. A total of 180 patients were identified, 136 with pleural and 37 with peritoneal mesothelioma. There were five pericardial and two testicular primaries. Of the two decades included in the study, later patients were significantly older, with a more advanced disease stage, and a lower performance status than those accrued early in the study. Factors at diagnosis associated with a significantly prolonged survival for all patients with mesothelioma included a 0 to 1 performance status, absence of chest pain, age less than 50 years, and epithelial histology. Factors at diagnosis associated with prolonged survival for the subset of patients with pleural mesothelioma included epithelial histology, 0 to 1 performance status, the absence of chest pain, an interval of greater than 6 months from onset of symptoms, and treatment with chemotherapy and pleuropneumonectomy. This last result must be interpreted with caution, since this was not a randomized study.

Prognostic factors predictive of survival for truncal and retroperitoneal soft-tissue sarcoma

ObjectiveThe authors identified prognostic factors relevant to clinical outcomes (especially survival) in truncal and retroperitoneal soft-tissue sarcoma. Summary Background DataSummary Background Data results can be used to optimize surgical management and select patients most likely to benefit from novel therapeutic strategies in future trials. MethodsA retrospective analysis was performed of a prospectively compiled database of 183 consecutive patients with truncal and retroperitoneal sarcomas seen at the Brigham and Womens Hospital and the Dana Farber Cancer Institute between 1970 to 1994. ResultsResults truncal sarcoma, multivariate analysis showed that high-grade histology was associated with an eightfold increased risk of death compared with low-grade histology (p = 0.001). In addition to grade, gross positive margin of resection (p = 0.001), microscopic positive margin (p = 0.023), and tumors greater than 5 cm in size (p = 0.018) were important independent prognostic factors for survival. In this series, postoperative radiation therapy for truncal sarcoma was associated with a 2.4-fold decreased risk of death compared with truncal sarcoma patients receiving no adjuvant radiation therapy, having adjusted for the other prognostic factors (p = 0.030).In contrast, for retroperitoneal sarcoma, multivariate analysis showed that high-grade and intermediate-grade histology were associated with a five- to sixfold increased risk of death compared with low-grade histology (p = 0.009). In addition to grade, gross positive margin of resection (p = 0.001) and microscopic positive margin (p = 0.004) were important independent prognostic factors for survival in retroperitoneal sarcoma. Patients who received either preoperative or postoperative chemotherapy for retroperitoneal sarcoma had a 4.6-fold (p = 0.002) and 3-fold (p = 0.010) increased risk of death, respectively, compared with patients receiving no adjuvant chemotherapy, having adjusted for the other prognostic factors. ConclusionsConclusions histologic grade and the margin of resection are prognostic for survival in both truncal and retroperitoneal soft-tissue sarcoma. Tumor size was an independent prognostic factor for truncal sarcoma, but not for retroperitoneal sarcoma. Postoperative adjuvant radiation was beneficial to overall survival for truncal sarcoa. In this series of patients receiving a heterogeneous mixture of chemotherapeutic regimens-either as preoperative “neoadjuvant” therpy or as postoperative “adjuvant” therapy, there were no beneficial effects on survival compared with nonrandomized patients not receiving chemotherapy.

The separation of benign and malignant mesothelial proliferations

The separation of benign from malignant mesothelial proliferations has emerged as a major problem in the pathology of the serosal membranes. For both epithelial and spindle cell mesothelial processes, true stromal invasion is the most accurate indicator of malignancy, but stromal invasion is often difficult to assess, especially in small biopsies. In the pleural cavity, deep penetration of a thickened and fibrotic pleura or penetration of mesothelial cells into the fat of the chest wall are good indicators of malignancy; however, superficial entrapment of mesothelial cells and glands by organizing effusions is common in benign reactions and needs to be distinguished from invasion. In the peritoneal cavity, invasion of fat or of organ walls is again the most reliable indicator of malignancy, but entrapment of benign cells in organizing granulation tissue or between fat lobules is frequent and confusing. Proliferations confined to the pleural or peritoneal space, particularly linear arrays of atypical mesothelial cells on the free surface, should not be called malignant in the absence of unequivocal invasion. Cytologic atypia is often not helpful in separating benign from malignant reactions, because benign processes are commonly atypical and mesotheliomas are often deceptively monotonous. Densely packed mesothelial cells within the pleural space are frequent in benign reactions, but densely packed mesothelial cells within the stroma favor a diagnosis of malignancy. Organizing effusions (fibrous pleurisy) typically show zonation with high cellularity and cytologic atypia toward the pleural space and increasing fibrosis with decreasing cellularity and lesser atypia toward the chest wall, whereas sarcomatous (including desmoplastic) mesotheliomas do not demonstrate this type of zonation. Elongated capillaries perpendicular to the pleural surface are seen in organizing effusions but are not a feature of sarcomatous mesotheliomas. The combination of a paucicellular storiform pattern, plus invasion of the stroma (including fat and adjacent tissues), or bland necrosis, overtly sarcomatous foci, or distant metastases, is required for the diagnosis of desmoplastic mesothelioma. Necrosis is usually a sign of malignancy but is occasionally seen in benign mesothelial reactions. Keratin staining is useful in indicating the distribution of mesothelial cells, and particularly in demonstrating penetration of mesothelial cells into the stroma or adjacent structures, but is of no help in separating benign and malignant proliferations because both are keratin-positive. Although both p53 and EMA staining have been proposed as markers of mesothelial malignancy, in our experience they are not helpful for the individual case.

Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma.

PURPOSE We studied a multimodality approach using extrapleural pneumonectomy, chemotherapy, and radiotherapy in patients with malignant pleural mesothelioma. PATIENTS AND METHODS From 1980 to 1992, 52 selected patients, underwent treatment. Median age was 53 years (range, 33 to 69). Initial patient evaluation was performed by a multimodality team. Pathologic diagnosis was reviewed and confirmed before therapy. Patients with no medical contraindication and potentially resectable mesothelioma on computed tomography (CT) (magnetic resonance imaging [MRI] when it became available) received extrapleural pneumonectomy, cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy, and radiotherapy. RESULTS Perioperative morbidity and mortality rates were 17% and 5.8%, respectively. The overall median survival duration is 16 months (range, 1 month to 8 years). The 32 patients with epithelial histologic variant had 1-, 2-, and 3-year survival rates of 77%, 50%, and 42%, respectively. Patients with mixed and sarcomatous cell disease had 1- and 2-year survival rates of 45% and 7.5%; no patient lived longer than 25 months (P < .01). At resection, positive regional mediastinal lymph nodes were found in 13. Positive lymph nodes were associated with poorer survival than were negative nodes (P < .01). Patients with epithelial variant and negative mediastinal lymph nodes had a survival rate of 45% at 5 years. CONCLUSION Multimodality therapy including extrapleural pneumonectomy has acceptable morbidity and mortality for selected patients. Prolonged survival occurred in patients with epithelial histologic variant and negative mediastinal lymph nodes. These data provide a rationale for a revised staging system for malignant pleural mesothelioma; furthermore, they permit stratification of patients into groups likely to benefit from aggressive multimodality treatment.

Prognostic factors predictive of survival and local recurrence for extremity soft tissue sarcoma

ObjectiveThe authors sought to identify prognostic factors in the management of extremity soft tissue sarcoma. Summary Background DataThe surgical management of soft tissue sarcoma has evolved because of advances in therapy, resulting in increased limb preservation and quality of life. However, identifying a subset of patients most likely to benefit from adjuvant chemotherapy has been difficult to achieve. MethodsA retrospective analysis of a prospective data base of 182 patients with extremity sarcomas from 1970 to 1992 was performed. ResultsA histologic diagnosis of Ewings sarcoma, synovial sarcoma, and angiosarcoma was associated with a 13-fold increased risk of death compared with liposarcoma, fibrosarcoma, and malignant peripheral nerve sheath histologic types after having adjusted for the other prognostic factors (p < 0.001). In addition to histotogic type, high-grade sarcomas (p = 0.018), sarcomas greater than 10 cm in size (p = 0.006), and age at diagnosis (p = 0.016) were found to be important prognostic factors for survival but not for local recurrence. For the first time to their knowledge, the authors showed that mean mitotic activity has prognostic value after having adjusted for other prognostic factors, such as grade (p = 0.005). The only prognostic factors predictive for local recurrence were whether the patient presented with locally recurrent disease (p = 0.0001) or had microscopically positive margins (p = 0.052). ConclusionsThe use of mitotic activity along with grade, size, histologic type, and age at diagnosis is prognostic for survival in extremity soft tissue sarcoma. The use of an objective pathologic feature, such as mean mitotic activity, is also useful in selecting patients for future systemic neoadjuvant or adjuvant trials and primary therapy.

Synovial sarcoma: prognostic significance of tumor size, margin of resection, and mitotic activity for survival.

PURPOSE The present study serves to describe outcomes-based prognostic variables characteristic of synovial cell sarcoma. PATIENTS AND METHODS An analysis was performed of a prospectively compiled data base of 48 consecutive patients with extremity and truncal synovial sarcomas seen between 1966 and 1994. RESULTS No local recurrences were observed among 27 patients who presented with localized primary disease. Patients with synovial sarcoma less than 5 cm in size has a cancer-specific survival rate at 10 years of 100%, compared with a 10-year survival rate of 32% and 0% for those with sarcoma 5 to 10 cm and greater than 10 cm, respectively (P = .002). Patients with synovial sarcoma with less than 10 mitoses per 10 high-power fields (hpf) had a 10-year cancer-specific survival rate of 46%, compared with a 10-year survival rate of 14% for those with sarcomas with greater than 10 mitoses per hpf (P = .04). Patients with a clean margin of excision were found to have a 10-year cancer-specific survival rate of 43%, compared with 0% for those with microscopic positive margins (P = .03). Among 14 patients treated with neoadjuvant chemotherapy, seven (50%) had objective responses. CONCLUSION Local control for patients with nonmetastatic disease was excellent. The overall cancer-specific survival rate for patients with localized synovial sarcoma was 34% at 10 years. Primary tumor size, margin of resection, and mean mitotic activity were prognostic factors for survival in synovial sarcoma. There was a high objective response rate to treatment with neoadjuvant chemotherapy; however, there was no detectable beneficial effects on survival in the subset of patients treated with chemotherapy versus nonrandomized patients who received no chemotherapy. Patients with synovial sarcoma > or = 5 cm in size, microscopic positive margins, and/or mean mitotic activity greater than 10 mitoses per 10 hpf should be targeted for new therapeutic studies.

Malignant mesothelioma: Ultrastructural distinction from adenocarcinoma

Mesotheliomas and metastatic adenocarcinomas involving the pleura are frequently difficult to distinguish by light-microscopic and histochemical methods. In a double-blind study, we have compared ultrastructural features of 10 mesotheliomas of epithelial type and 10 adenocarcinomas from the lung, breast, and upper GI tract, i.e., sites known to give rise to metastases which mimic mesothelioma. Mesotheliomas were observed to have a significantly greater microvillus length/diameter ratio (LDR) than adenocarcinomas (p < 0.01) and more abundant intermediate filaments (p < 0.001). Mesotheliomas had more complex microvilli than adenocarcinomas, whereas adenocarcinomas had rootlets (2/10 cases) and lamellar inclusion bodies (2/10 cases), both of which were absent in the mesotheliomas. This study provides quantitative and qualitative ultrastructural features of potential utility in the differential diagnosis of pleural mesotheliomas and adenocarcinomas.