University of Virginia Health System

Leukemic Phase of Follicular Lymphoma
(Leukolymphosarcoma)

(a) Follicular lymphoma cells in the peripheral blood. Both small cleaved and large cleaved cells are present- Peripheral blood smear, Wright-Giemsa stain, 1000x

(b) Large cleaved follicular lymphoma cell with nucleolus- Peripheral blood smear, Wright Giemsa stain, 1000x

(c) Medium-sized follicular lymphoma cell with scant cytoplasm- Peripheral blood smear, Wright Giemsa stain, 1000x

Description:

A leukemic phase at diagnosis or during the course of follicular lymphomas occurs in up to 15% or more cases, and was originally referred to as leukosarcoma (Sternberg C. Zur Kenntris des Chloroms (Chloromyelosarkam). Beitr path allg Path 37:437, 1905.) Other designations have included leukolymphosarcoma, lymphosarcoma cell leukemia, and leukemic phase of non-Hodgkin's lymphoma.

The morphologic appearance of the cells vary from small cleaved lymphocytes (centrocytes, Grade 1 follicular lymphoma cells) to large cleaved or non-cleaved lymphocytes (centroblasts, Grade 3 follicular lymphoma cells). A mixture of both is often present, as the case shown demonstrates (a,b,c). The small cleaved cells are 1½-2 times that of small lymphocytes, and have more cytoplasm which ranges in color from grey-blue to light blue. The nucleus is characteristically clefted, and the nuclear chromatin is clumped, and nucleoli may or may not be visible (b). The large cleaved and non-cleaved cells frequently have nucleoli, and the chromatin is more immature, but still clumped. The cytoplasm is more basophilic. The bone marrow is frequently involved and the pattern on biopsy is distinctive: paratrebecular in location. Peripheral blood involvement may be seen in the absence of bone marrow involvement. The number of cells seen in the peripheral blood is variable, but usually minimal.

Immunophenotype:

The clonal cells are CD19+, CD10+, Bcl2+, CD5-, CD23-, and FMC 7-. CD10 positivity represents an important differential diagnostic finding, but it is not always positive. The follicular or nodular pattern of lymph node involvement is the single most important pathologic finding. The paratrabecular pattern of bone marrow involvement is also very distinctive.

Cytogenetics:

The signature cytogenetic finding is the t(14;18) involving the Bcl-2 gene.

Clinical and Laboratory Manifestations:

The great majority of patients with follicular lymphomas, with or without peripheral blood involvement, present at an advanced stage, involving mainly lymph nodes, and usually asymptomatic. The course is an indolent one in many patients, not requiring treatment for many years. The finding of peripheral blood or bone marrow involvement does not alter the course of the disease in most instances. Extranodal disease is distinctly unusual unless transformation to diffuse large cell B cell lymphoma occurs, an event that does happen in approximately 30% of cases. The one exception is a distinct subset that involves the skin, particularly the scalp (Santucci M, et al. Cancer 67:2311, 1991) that is referred to as cutaneous follicular lymphoma.

Prognosis:

Very good. Response to a variety of therapeutic modalities (e.g. single agents, combination chemotherapy, immunotherapy, immunoradiotherapy, radiotherapy) usually is good, but none result in prolonged survival if used in asymptomatic patients. Curability is possible only with allogeneic bone marrow transplantation, and maybe in a few patients with early stage disease (Stage I or II) treated with radiation therapy. Early stage disease at diagnosis is confirmed in only a very small percentage of patients if a thorough staging is performed using presently available studies (e.g. immunophenotyping, molecular genetics, PET-CT scans.)

General References:

• Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of hematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumors, Lyon, France: IARC Press, 2001 
• Come ES, Jaffe ES, Anderson JC, et al. Non-Hodgkin lymphoma in leukemic phase. Am J Med 69:667, 1980
• Issacs R. Lymphosarcoma cell leukemia. Am Intern Med 11:657, 1937
• Rosenberg SA, Diamond HD, Jaslowitz B, et al. Lymphosarcoma: a review of 1269 cases. Medicine (Baltimore) 40:31, 1961

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