Classification of Hodgkin's disease: yesterday, today and tomorrow.
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Biomedical subjects
Publications and source records attributed to J E Ultmann.
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Unknown primary malignancy (UPM) is not a disease entity. Rather, it represents a variety of different metastatic, malignant neoplasms all presenting with either an occult primary or having such a highly undifferentiated histologic appearance that an accurate pathologic classification on routine hematoxylin-eosin section is not possible. UPM is a spectrum of malignancies that includes those that are treatable and curable and those for which no specific treatment exists. For the physician, a diagnosis of UPM represents a beginning rather than an end. The minimal workup of such patients includes a thorough history and physical examination, complete blood counts, urine analysis, multichannel chemistries, a chest radiograph, and computed tomography of the abdomen and pelvis. Having completed this workup, further tests are unnecessary and unwarranted unless specific symptoms or physical signs exist. Once the aforementioned workup is completed, the physician must communicate frequently and freely with the pathologist as further diagnostic tests will be laboratory based and include electron microscopy, histochemical stains, and immunocytochemistries. Immunocytochemistries are relatively new laboratory procedures which have made a significant contribution in the accurate pathologic diagnosis of a tissue specimen that in years past would have been classified as an unidentified malignant neoplasm. An initial panel of immunocytochemistries (vimentin, cytokeratin, CEA, and common leukocyte antigen) should be performed on the tissue block in patients with UPM as they provide direction in the accurate classification of the malignant neoplasm. Chromosomal analysis of tissue is useful in the recognition of lymphomas or soft-tissue sarcomas which would otherwise be classified as UPM. In years to come, when specific DNA probes capable of identifying specific chromosomal rearrangeaments are widely available, pathologic classification of UPM will be performed on a molecular level. Some unknown primary malignancies are treatable and potentially curable. These include large cell lymphoma, extragonadal germ cell malignancies, squamous cell carcinoma metastatic to cervical lymph nodes without an obvious primary, metastatic adenocarcinoma to axillary lymph nodes in women (invariably on occult breast primary), and malignant ascites in women, which usually represents ovarian cancer. Metastatic adenocarcinoma of unknown primary origin, with the exception noted above and the rare presentation of an occult prostate cancer as UPM, is an ultimately fatal malignancy with a relatively shor clinical course.(ABSTRACT TRUNCATED AT 400 WORDS)
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Between September 1983 and April 1985, 15 patients with previously untreated intermediate and high grade lymphoma were treated with COMLA/ABP (cyclophosphamide, vincristine, cytarabine, methotrexate, leucovorin, adriamycin, bleomycin, prednisone). There were nine males and six females; age ranged between 36 and 77 years (median, 58). Histologic diagnoses included five patients with diffuse large cell, six patients with immunoblastic, three patients with composite, and one patient with follicular large cell with diffuse areas. Following therapy, 10 patients (67%; 95% confidence interval (Cl), 43-91%) achieved a complete remission (CR) including five of six patients with immunoblastic; three patients (20%) had a partial remission, and two patients (14%) had no response. Toxicity was acceptable. After a minimum follow up of 4 years, there has been only one relapse which occurred 7 months after CR. The 4-year survival for all 15 patients is 65% (95% Cl, 40-89%). The COMLA/APB program produced a high rate of complete and durable remissions especially among patients with immunoblastic lymphoma.
Sixty-seven previously untreated patients with Hodgkin's disease, pathologic stages I and II, seen during a 7-year period were evaluted with respect to initial staging and treatment, as well as relapse and retreatment results. The initial treatment consisted of radiation therapy (RT) to an involved field (IF) or an extended field (EF) for patients with stages IA and IIA, or RT and, in recent cases, combination chemotherapy [cyclophosphamide, Oncovin, procarbazine, and prednisone (COPP)] for patients with stages IB and IIB. Nineteen of the 67 patients relapsed (28%), including 11 of 56 patients with stages IA and IIA (20%) and 8 of 11 patients with stages IB and IIB (73%). Seventeen of the 19 relapses occurred within 24 months after completion of the initial therapy (89%). The relapse-free survival at 5 years was 75% for the A patients and 25% for the B patients. The actuarial survival of stage IA and stage IIA patients at 5 years was 91%; there was no significant difference between patients treated initially with either IF or EF. The actuarial survival at 5 years for the patients with stages IB and IIB was 88%, as most responded to a second program of induction therapy. No correlation could be found between the pattern of relapse and the initial pathologic stage or the mode of treatment.
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The preferred histopathological classification of Hodgkin's disease (HD) is that suggested by Lukes and Butler as modified at the Rye Symposium; the histologic subtypes are highly reproducible and correlate well with the anatomic sites of involvement, clinical stage, and survival. The accuracy of the bipedal lymphangiogram, 67gallium scan, and ultrasonography in predicting abdominal involvement by HD is 90% , 50%, and 88%, respectively. Staging laparotomy remains the most accurate method of detecting intra-abdominal disease and has added immensely to new concepts in the management of HD. These concepts suggest that patients with nodal disease limited to the celiac axis or upper para-aortic areas (substage III1) or pathologic stage (PS) IIIS+N-A, when treated with extended field radiotherapy alone have survival rates comparable to PS IIA patients. In contrast, patients in PS IIIA with lower abdominal nodal disease (substage III2), regardless of splenic involvement, have a prognosis comparable to PS IV disease. Thus, there may only be two stages of HD, those curable with extended mantle or smaller radiotherapy fields alone, and those requiring chemotherapy with or without supplemental radiotherapy.
Four patients with advanced diffuse histiocytic lymphoma who developed lactic acidosis are described. All four patients demonstrated disturbed liver function tests. In two of the patients, the lactic acidosis was unresponsive to treatment. The third patient responded successfully to the early initiation of combination chemotherapy with achievement of a clinical remission and correction of the lactic acidosis. The fourth patient responded to the initiation of chemotherapy with abatement of his lactic acidosis, but expired probably as the result of a pulmonary embolus. It seems likely that extensive hepatic infiltration may be one of the factors contributing to lactic acidosis in patients with diffuse histiocytic lymphoma. The early initiation of antineoplastic therapy may be important in the management of patients with histiocytic lymphoma and lactic acidosis.
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Patients with malignant lymphoma, diffuse type, have an unfavorable prognosis when compared to those patients with modular patterns. Prior to the introduction of combination chemotherapy, 50% survival rates for MC-D or PDL-D were about 2 years, HL-D about 1 year. Aggressive combination chemotherapy for advanced MC-D or PDL-D results in complete remission rates of 22-82%, with median survivals of 1-2 years. Patients with localized HL-D are probably curable with radiotherapy alone in 75% of cases. Patients with advanced disease are best treated with intensive combination chemotherapy, achieving a long-lasting complete remission in over one-half of cases, with median survivals now at 1-3 years. Many of these patients are probably cured, central nervous system relapse may now be a concern. The results of treatment of advanced histiocytic lymphoma are now approaching the results reported for advanced Hodgkin disease.
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Appropriate selection of therapy for patients with non-Hodgkin lymphoma requires an understanding of the various histologic classifications as well as knowledge of the role of clinical and pathologic staging. The histologic classification of the malignant lymphomas proposed by Rappaport is reviewed. The Ann Arbor Staging System is outlined and its application to NHLs analyzed. Recommendations for clinical staging procedures together with the accuracy of diagnostic tests in the NHL are discussed briefly.
Twenty of 65 patients with diffuse histiocytic lymphoma were identified by staging laparotomy as being in pathologic stages (PS) I, I(E), II, II(E). Six of the 20 patients were treated with total nodal, 10 with extended mantle, and four with involved-field radiotherapy. The survival rate and relapse-free survival at five years were 71% and 78%, respectively. All relapses occurred within the first year and were confined to patients with PS II disease and four or more sites of involvement. Accurate pathologic staging identifies patients who are potentially curable with radiotherapy. Further studies are required to determine the treatment necessary to achieve cure in PS II patients with more than four sites of involvement.
A patient with rapidly fatal hypereosinophilic syndrome and a bone marrow chromosomal abnormality, 49,XYY,t(3:5),+8,+mar, is described. Scanning and transmission electron microscopy of eosinophils failed to reveal any significant abnormalities. Previous cytogenetic data on patients with hypereosinophilic syndrome have been deficient in that few studies have been performed with banding technics. These technics may help in the classification of hypereosinophilic syndrome and predict which patients will have a rapidly fatal course.
Chronic lymphocytic leukaemia is a disorder with variable clinical presentation, but with constant and easily recognizable morphological features. The majority of cases are of B-cell lineage, the cells being characterized by IgM and IgD surface markers. In occasional cases monoclonal gammopathies with idiotypes identical to those of the SIg are produced. Some cases of CLL may be confused with Waldenström's macroglobulinaemia. The clinical and morphological features of certain other lymphoproliferative disorders have been summarized. Finally, a progression of B-cell differentiation along an immunoexpressive spectrum has been described and the relative position of CLL defined. A correlation of cell morphology and function is possible in most cases. The possibility that CLL may terminate in an acute blastic crisis or histiocytic lymphoma is raised. It is emphasized that LPD include a wide range of diseases, some being non-malignant, others of questionable malignancy, and still others being frankly malignant. Clinical, morphological and immunological data are required for diagnosis in some cases.