Pathologic quiz case: An elderly woman with lymphocytosis.

An 85-year-old African American woman was referred to the hematology-oncology clinic for evaluation of lymphocytosis in August 2000. Her past medical history was significant for rheumatoid arthritis that had caused chronic pain for years. Lymphocytosis (lymphocyte count, 5312/μL) had been present for 4 months. She had noted fatigue since then without other symptoms. At that time, physical examination showed no evidence of lymphadenopathy. Radiographs and a computed tomography scan of the abdomen and pelvis did not show retroperitoneal or mediastinal lymphadenopathy or splenomegaly. Mild normocytic normochromic anemia was noted (hematocrit, 36%; hemoglobin concentration, 11.3 g/dL). There was no evidence of neutropenia (neutrophil count, 2407/μL). A presumptive diagnosis of chronic lymphocytic leukemia was made clinically. In May 2001, another complete blood count showed a white blood cell count of 7800/μL with 71% lymphocytes (absolute number, 5538/μL).In November 2001, test results indicated that the lymphocytosis had progressed; the lymphocyte count was 13 350/μL (89% white blood cells), and mild neutropenia was present (neutrophil count, 1500/μL). A review of the peripheral blood smear revealed that the majority of lymphocytes had atypical morphology with large atypical nuclei and abundant cytoplasm containing fine azurophilic granules (Figure 1). A flow cytometry study showed that 92% of the lymphocytes expressed CD2, CD3, and CD5, and most (85%) expressed CD4. The majority of these cells also expressed CD56 and CD57 but not CD7, CD16, or CD26. The representative histograms are shown in Figures 2 through 4.What is your diagnosis?In the current World Health Organization classification for lymphoid tumors, T-cell large granular lymphocyte leukemia (T-LGL) is defined as a heterogeneous disorder characterized by a persistent (>6-month) elevation of the number of peripheral blood large granular lymphocytes, usually to a value between 2000 and 20 000/μL (reference range, 223 ± 99/μL), without a clearly identified cause.1 The number of large granular lymphocytes required for diagnosis remains controversial; however, a value of greater than 5000/μL is considered to be diagnostic, and a value of greater than 2000/μL is considered to be consistent with the diagnosis.2 Clinically, the disease occurs in adults with a median age of 55 years and has an equal male-to-female distribution. Neutropenia with or without anemia is a frequent disease feature. Recurrent infections due to neutropenia are the main reason for medical attention. Some patients present with moderate splenomegaly, yet lymphadenopathy is very rare. About 40% of cases are asymptomatic at presentation. Of particular interest, as seen in our patient, is the co-occurrence of rheumatoid arthritis in patients with T-LGL (with rheumatoid arthritis usually occurring first).3Morphologically, the circulating neoplastic lymphocytes are characterized by abundant cytoplasm with fine or coarse azurophilic granules. The granules in the lymphocytes often exhibit a characteristic ultrastructural appearance described as parallel tubular arrays.4 In addition, they contain a number of proteins that play a role in cytolysis, such as perforin and granzyme B. T-LGL may involve bone marrow, spleen, and liver. Bone marrow involvement is typically interstitial and rarely shows a nodular pattern. Usually, the extent of involvement is less than 50% of the marrow cellularity. Characteristic findings in splenic involvement include infiltration of the lymphocytic red pulp cords and frequent reactive germinal follicles. Touch imprints of splenic tissue are important for showing the presence of large granular lymphocyte morphology. Plasmacytosis of the splenic red pulp is frequently observed.5 Liver involvement is characterized by a lymphocytic infiltration of hepatic sinusoids with portal area involvement in extensive disease.The neoplastic lymphocytes in T-LGL have a mature T-cell immunophenotype. In the most common variant, 80% of cases, the cells express CD3 and CD8 but do not express CD4.6 Other rare variants include (1) CD3+, CD4+, and CD8−, (2) CD3+, CD4+, and CD8+, and (3) CD3+, CD4−, and CD8−. The cells are usually TIA-1 positive, whereas they variably express CD56 and CD57. In the common type of T-LGL, the cells often express CD57.On the genetic level, by definition, T-LGL is clonal, which is documented by T-cell receptor (TCR) gene rearrangement studies.7 Most cases have TCRβ chain gene rearrangement, whereas the minority show a TCRγ chain gene rearrangement. The gene rearrangement study is particularly useful in patients with a large granular lymphocyte count of 2000/μL or less, since demonstration of an expansion of a restricted clonal large granular lymphocyte subset has been suggested to be evidence for the diagnosis.2 There is no unique karyotypic abnormality in T-LGL, but chromosomal translocations have been described in a minority of cases.8In the current case, the morphology and the immunophenotypic pattern of circulating neoplastic lymphocytes were consistent with those of T-LGL (one of the rare variants: CD3+ and CD4+ but CD8−). Deletion of CD7 and CD26 in these lymphocytes further supports their neoplastic nature. The clinical picture of a progressive increase in the number of large granular lymphocytes, from 5312 to 13 350/μL over 15 months, with development of neutropenia confirms the diagnosis of T-LGL. The main differential diagnoses for our case included aggressive natural killer (NK)-large granular lymphocyte leukemia (NK-LGL) and reactive large granular lymphocyte lymphocytosis. NK-LGL has morphologic features very similar to those of T-LGL but is surface CD3− and usually CD16+. Clinically, NK-LGL usually has an acute clinical course, with a rapid increase in large granular lymphocyte counts over a few weeks. Anemia, thrombocytopenia, and massive hepatosplenomegaly are more common and pronounced in NK-LGL than in T-LGL. Patients with reactive large granular lymphocyte lymphocytosis have increased numbers of large granular lymphocytes with the immunophenotype of NK cells (surface CD3−). This disease has a chronic and indolent clinical course in contrast to NK-LGL.X-linked gene analysis has supported a polyclonal NK-cell proliferation in patients with T-LGL.9 The vast majority of cases that were thought to be reactive large granular lymphocyte lymphocytosis of T-cell origin in the old literature are indeed T-LGL since almost all cases, even those with large granular lymphocyte counts of 2000/μL, or less, show clonal TCR gene rearrangement by molecular methods.210T-LGL typically has an indolent course. Morbidity is associated with the neutropenia, but mortality is uncommon. Usually, no treatment is required; however, patients who require treatment may benefit from cyclosporin A and methotrexate. Infrequently, splenectomy is performed in patients with splenomegaly, but this does not reduce the cytopenia.