Henrik B. Schultz

Risk of acute nonlymphocytic leukemia and preleukemia in patients treated with cyclophosphamide for non-Hodgkin's lymphomas. Comparison with results obtained in patients treated for Hodgkin's disease and ovarian carcinoma with other alkylating agents.

Of 602 patients treated for non-Hodgkins lymphomas, 9 developed overt acute nonlymphocytic leukemia or preleukemia with refractory cytopenia and cytogenetic abnormalities of the bone marrow. A Kaplan-Meier estimate of the cumulative probability of leukemic complications was 6.3 +/- 2.6% (mean +/- SE) 7 years after start of treatment. All 9 patients with leukemic complications belong to a major subgroup of 498 patients treated with alkylating agents, predominantly cyclophosphamide. The risk of leukemic complications in this subgroup was compared with the risk in 312 patients treated with other alkylating agents for Hodgkins disease, and with the risk in 553 patients treated with dihydroxybusulfan for ovarian carcinoma. Cumulative 9-year risks were 8.0 +/- 3.3%, 12.8 +/- 3.5%, and 7.1 +/- 1.9%, respectively. The general risk of secondary leukemia after long-term treatment with alkylating agents ranges from 1% to 1.5% per year from 2 to at least 9 years after start of treatment.

Follicular low-grade non-Hodgkin's lymphoma: Long-term outcome with or without tumor progression

Long‐term outcome for 127 patients with follicular low‐grade lymphoma was investigated. Therapy included radiotherapy (n = 23), low toxicity chemotherapy with or without radiotherapy (n = 76), or more intensive chemotherapy (n = 22). 6 patients had no initial therapy. Complete remission was obtained in 67% of patients. For patients under 60 years of age median survival was 8.7 yr compared with 3.8 yr for older patients, but survival from lymphoma was identical for the two age‐groups: 75% at 5 yr, and 58% at 10 yr. The relatively low tumor mortality contrasted with a relapse‐free survival of 30% at 10 yr, and relapse 8–9 yr after first remission. Examining the disease topography and the stability of histologic subtype in 78 patients with recurrent lymphoma, two types of relapse with different prognoses were identified: 1) with tumor progression (lymphoma dissemination to atypical extranodal sites and/or histologic conversion to an intermediate/high‐grade lymphoma) seen in 56% of patients with a survival from lymphoma of 13% at 10 yr; and 2) without tumor progression (involvement of nodal sites, and unchanged histology) seen in 44% with a survival from lymphoma of 77% at 10 yr. Actuarial risk of tumor progression was 44% at 5 yr, and 67% at 10 yr. Except from the negative impact of a large tumor burden, it was not possible to identify patients with high risk for tumor progression. More important than all pretreatment factors was poor response to initial therapy (p = 0.0001). Due to lack of reliable risk factors, it is recommended that all younger patients be treated with the intention of achieving complete remission; a significant fraction might be curable.

Comparison of the working formulation of non‐Hodgkin's lymphoma with the Rappaport, Kiel, and Lukes & Collins classifications. Translational value and prognostic significance based on review of 658 patients treated at a single institution

Six hundred fifty‐eight cases of previously untreated non‐Hodgkins lymphoma seen between 1970 and 1979 at the Medical Department, the Finsen Institute, were the basis for a comparative study of the prognostic value of the Rappaport, Kiel, and Lukes & Collins classifications and the new translation system, the Working Formulation of Non‐Hodgkins Lymphoma. Each histopathologic system proved equally effective in separating patients into subgroups with a spectrum of prognoses ranging from a median survival of <1 year to >7 years. The established classifications were compared with the Working Formulation in order to evaluate its translational value. The Working Formulation was more similar to the Rappaport and the Lukes & Collins systems than to the Kiel system, since 82%, 89%, and 75% of the cases, respectively, were translatable following the guidelines outlined in the National Cancer Institute (NCI)‐sponsored study. Similarities among the four systems were demonstrated in lymphomas with follicular growth pattern, and in diffuse lymphomas composed of small mature appearing lymphocytes or small cleaved lymphocytes. Incongruity among the systems was more marked in lymphomas composed of large lymphoid cells or in lymphomas of mixed cellular composition. A comparison was performed for each classification against the Working Formulation. All such subdivided subsets were tested for prognostic heterogeneity and the following conclusions were reached: (1) the diffuse poorly differentiated lymphocytic category of Rappaport was separated into two subgroups (malignant lymphoma [ML] small cleaved cell and ML lymphoblastic) with different prognoses (P = 0.01); (2) the diffuse “histiocytic” lymphomas were prognostically homogeneous, since none of the newer systems were able to identify subpopulations with significantly different prognoses; (3) the subtypes of the Kiel classification were prognostically homogeneous; (4) the only weakness of the Lukes & Collins classification was the undefined cell subtype, encompassing two populations with different prognoses; and (5) the importance of follicular growth pattern was confirmed for small cleaved cell and mixed cell cytology, whereas large cell cytology implied a poor prognosis regardless of pattern. By the use of the Cox regression model it could be demonstrated that the Working Formulation can substitute any of the established classifications in terms of prognostic value.

Non-Hodgkin's lymphomas: Recent concepts in classification and treatment

The non‐Hodgkins lymphomas (NHL) is a heterogeneous group of tumors derived from B and T lymphocytes and their precursors. In this review we have used a classification scheme of 5 main categories: 1. Follicular lymphomas, 2a. small lymphocytic cell (CLL or immunocytomas), 2b. diffuse small cleaved cell including intermediate lymphocytic and mantle zone NHL, 3. large cell NHL, 4. early B cell (Burkitts and non‐Burkitts), 5. precursor cell (lymphoblastic lymphomas). Classification of non‐leukemic post‐thymic T cell NHL is still controversial. Prognostic factors are parameters of tumor burden, proliferative activity, and the condition of the patient. Actual step of tumor progression, the dose intensity of chemotherapy, and the rapidity of tumor regression may also be of importance for outcome. The optimal therapy for follicular NHL remains to be defined. However, the inevitable course of tumor progression and the fact that only achievement of CR offers the chance of a significant fraction of patients being disease‐free leads to the recommendation to treat all younger patients initially. Patients with large cell NHL regardless of stage should be treated with combination chemotherapy. The CR rates have increased with the use of more dose‐intensive regimens suggesting that prognosis for high‐risk subsets might be further improved using high‐dose chemotherapy with autologous bone marrow transplantation as first‐line therapy.

Application of quantifiable criteria in the Lukes and Collins classification of non-Hodgkin's lymphomas

Measurements of nuclear size and differential counts among six lymphoma cell types were performed on H & E stained sections. In differential counting, the definition of cell types was based on nuclear shape, chromatin pattern, and nucleoli. In a pilot study comprising 93 patients we found actual nuclear size inadequate for use in lymphoma classification. This was due to: 1. great overlap among cytological types; 2. no independent prognostic value of mean nuclear area; 3. contradictory terminology; the large cleaved type belonging to the small cell category (mean nuclear area below 40 μm2), and the small non-cleaved type belonging to the large cell category (mean nuclear area above 40 μm2). Differential counting - requiring about 10 min - was an easy way to meet the need for a more objective evaluation of the cellular composition in non-Hodgkins lymphomas. Quantifiable criteria based on differential counts were applicable in subclassification of three T-cell and seven B-cell types with an intraobserver reproducibility of 80%. More than 25% “large” cell types in a differential count implied an unfavourable prognosis. In test material, using a semi-morphometric classification, a correct prognostic category was obtained in 92% of 461 lymphomas and correct sub-classification obtained in 68%.

Prognostic significance of differential cell counts in non-Hodgkin's lymphomas.

The use of differential counting on H & E stained sections is proposed as a simple means to define low grade malignant and high grade malignant cytologic categories in non‐Hodgkins lymphomas. Differential counts were performed in lymphoma biopsies from 6 16 cases. In each biopsy we counted 100 lymphoma cells and classified each cell as belonging to a “small”, “medium‐sized”, or “large” cell type. The results indicate the presence of two prognostically distinct cytologic categories: a low grade and a high grade malignant. Lymphomas with less than 10%“large” cells represented low grade malignant cytology. Included in this category were also the, mainly follicular, lymphomas with more then 70%“medium‐sized” cells (up to about 25%“large” cells). In addition to the cytologic category, the architectural pattern is of major prognostic importance. We recommend the use of three prognostic categories in non‐Hodgkins lymphomas: I) Favourable architecture + favourable cytology. II) Unfavourable architecture + favourable cytology. III) Unfavourable cytology.

A simplified working formulation of non‐Hodgkin's lymphomas based on quantifiable histologic criteria

Quantifiable criteria for a Simplified Working Formulation of non‐Hodgkins lymphomas are proposed. Biopsy specimens from 582 patients followed from 8.5 to 18.0 years were classified according to the Working Formulation. In addition, on hematoxylin and eosin‐stained histologic sections, differential counts among six lymphoma cell types were performed. In each lymphoma 100 cells were counted from representative areas. The intralymphoma variation observed by this method was insignificant for the reproducibility of classification. Five histologic types were defined: (1) follicular small cell (⩽25% large cells), (2) follicular large cell (>25% large cells), (3) diffuse small cell (⩽10% large cells), (4) diffuse large cell (>10% large cells), and (5) lymphoblastic (>20% lymphoblasts). These criteria had clinical significance with regard to prognosis, leukemic conversion, and meningeal involvement. The intraobserver and interobserver reproducibility of the Simplified Working Formulation was, respectively, 91% and 88%. Cancer 64:2532–2540, 1989.

Comparison of the Working Formulation of non-Hodgkin’s lymphoma with the Rappaport, the Kiel, and the Lukes-Collins Classifications. Correlations and prognostic value

The Rappaport classification of non-Hodgkin’s lymphoma [1] gained universal acceptance as a valuable basic diagnostic language for communication of therapeutic results among medical centers in the period 1968–75. Recognition that non-Hodgkin’s lymphomas represent neoplasms of the lymphocytic immune system has resulted in new classifications based upon modern concepts of the T- and B-lymphocyte systems [2, 3]. Other newer classification schemes have challenged the terminology used by Rappaport [4–6], and the Rappaport system itself has been modified several times [7–9]. The existence and the use of many histologic classifications for the non-Hodgkin’s lymphomas prompted the United States National Cancer Institute to sponsor a large international multi-institutional clinicopathologic study comparing six classifications. The results were published in 1982, and two important conclusions were reached [10]: ‘First, each system is successful in separating a large group of patients into subgroups with a spectrum of prognoses varying from good to poor survival. Second, no system appears superior to any other in this respect’. Based on this study, the investigators reached consensus on a ‘Working Formulation of non-Hodgkin’s Lymphoma for Clinical Usage’.