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The chronic leukemias of lymphoid origin, part 1.

Chronic leukemias are a complex group of blood disorders that can be quite insidious in their appearance. They may go unrecognized by the patient and may only be discovered by chance screening or as part of a work-up for other symptoms of several months' duration. Evaluation of a chronic leukemia can be relatively straightforward and inexpensive, provided it is accurately diagnosed. The conclusive diagnosis of any of the chronic leukemias requires a skilled morphologist, but early consideration of these disorders and prompt referral can result not only in more efficient patient management, but also in considerable cost savings to the laboratory and hospital. Once a diagnosis of a chronic leukemia is made, the laboratory supervisor, armed with knowledge of the disorders, can help guide decisions on the extent of laboratory testing to ensure that appropriate and cost-effective choices are made.

Leukemic disorders are broadly classified into acute and chronic forms. The chronic leukemias, which are the focus of this discussion, are genetically identical or clonal proliferations of myeloid or lymphoid cells which, in contrast to acute leukemias, are characterized by the accumulation of relatively more mature cells within the blood, bone marrow, and parenchymal organs. As their name implies, chronic leukemias have a longer clinical course than their acute counterparts. Consequently, with increasing life expectancy and recent scientific advances in treatment, it has become necessary to establish the diagnosis at the earliest possible opportunity.

Diagnosing chronic leukemia

A diagnosis of chronic leukemia may be first suspected in an older adult who is found to have an elevated white cell count but who is otherwise in good health. However, in the majority of patients, there will be some complaint related to an abnormal cellular infiltrate in the bone marrow, spleen or liver. Common symptoms include palpable or painful splenomegaly (enlargement of the spleen), vague bone pain, anemia, and hypercatabolic signs such as weight loss or fever. A physical examination will often reveal an enlarged spleen.or liver. Adenopathy (enlargement of the lymphatic glands) is usually not a feature in all cases.

Much of the diagnosis of chronic leukemia is based on the morphologic examination of the peripheral blood smear. The precise findings will vary depending on the type of chronic leukemia and often requires special stains, cytogenetic analysis, and clinical correlation for accurate interpretation. Bone marrow examination is often performed as part of the work-up. In general, the bone marrow examination must also be interpreted in conjunction with the clinical and cytogenetic findings and is not diagnostic by itself. Expert interpretation by a hematopathologist is generally required to accurately separate neoplastic disorders from reactive processes, subclassification of myeloproliferative disortiers, and separation of this group of disorders from myelodysplastic disorders. Similar problems are encountered in the diagnosis of lymphoproliferative disorders, although certain disorders such as hairy cell leukemia (HCL) can be quite distinctive morphologically. Table 1 illustrates a general classification scheme for the chronic leukemias.

In the following two-part discussion, key aspects of the morphologic approach to the diagnosis of both chronic lymphoproliferative and myeloproliferative disorders are presented. Part one describes representative examples of the chronic leukemias of lymphoid origin, while part two (to be published in an upcoming issue) will discuss chronic leukemias of myeloid origin.

The chronic leukemias are clonal disorders and typically present as a proliferation of mature lymphold cells. These disorders can be further subdivided into B- and Tcell disorders by using specific antibodies in a test process, known as immunophenotyping, which can be performed by flow cytometry on peripheral blood or bone marrow aspirates, or by staining paraffin sections using immunohistochemical techniques.

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) accounts for about 30% of all leukemias in the western hemisphere and is the most common leukemia of adults. The median age at diagnosis is 55 years. Asymptomatic lymphocytosis may be the only evidence of early evolving CLL. According to the International Workshop on Chronic Leukemia and a working group sponsored by the National Cancer Institute, a diagnosis of CLL can be made in the presence of sustained and absolute lymphocytosis of more than 5,000 cells per mL of at least 4 weeks duration, consisting of less than 55% immature forms (prolymphocytes) in the peripheral blood, CD5 (cluster designation 5) activity, evidence of light chain restriction, presence of low density surface immunoglobulin, and greater than 30% lymphocytes in the bone marrow.[1] The diagnosis can be made with lower peripheral counts if monoclonality is demonstrated.

Blood findings. Lymphocyte Counts of 600 x [10.sup.9]/L are not unusual in established CLL (in contrast, the normal range is 4-11 x [10.sup.9]/L), and lymphocytes may account for 99% of circulating white cells. Most lymphocytes in CLL are small, with round or indented nuclei. The nucleoli are indistinct, and chromatin is heavily clumped. Numerous smudge cells may be apparent. A complicating autoimmune hemolytic anemia may also be evident on the peripheral smear with anemia, numerous spherocytes, and polychromasia. Up to 10% of the cells may be larger and nucleolated, and if less than 55% of such cells are observed in a peripheral smear, a diagnosis of prolymphocytic transformation of CLL - a combination of CLL and prolymphocytic leukemia (PLL) - should be considered. A diagnosis of full blown PLL is usually associated with more than 55% circulating prolymphocytes.

Marrow findings. A bone marrow biopsy is seldom required for the diagnosis; however, patterns and degree of lymphocytic infiltration has prognostic significance.[2] An interstitial pattern is present in about 35% of cases. Changes are interstitial and nodular in 30% of cases, diffuse in 25%, and nodular in 10%. The worst prognostic group is one with a diffuse infiltrative pattern that reflects massive replacement of hematopoietic elements. Many of these patients require therapeutic intervention. Patients with a peripheral count consistent with CLL but less than 25% involvement of the bone marrow are considered to have B-cell small lymphocyte to lymphoma. However, there is no evidence that this separation has therapeutic or prognostic significance.

Immunophenotypic analysis. Flow cytometry has an indispensable role in the evaluation of chronic lymphoid leukemias and can often establish the diagnosis (see Table 2). The overwhelming majority of chronic lymphocytic leukemias represents clonal B-cell disorders; expresses CDS, CD19, CD20, and CD23; and tests negative for terminal deoxyneucleotidyl transferase (TdT) and CD38. Tumor cells demonstrate light chain restriction with weak surface immunoglobulin expression. Weak surface immunoglobulin expression is helpful in separating CLL from PLL and other small lymphocytic proliferations. CD23 is usually strongly expressed in CLL and helps separate CLL from mantle cell lymphoma that has peripheralized. An antigen defined by an antibody developed at Flinders Medical Center in Australia, FMC7, is another marker that is typically not expressed in CLL but reportedly correlates with prolymphocytic transformation. Again, concomitant evaluation of the peripheral smear is much more important in this assessment.

Chromosomal abnormalities. Cytogenetic analysis is infrequently requested in the diagnostic workup of CLL. Although these studies may have prognostic implications, the results rarely affect treatment strategies. Cytogenic studies are also quite costly. Reference laboratories are best used for karyotyping services by smaller hospitals. If karyotypic analysis is performed, the preferred specimen is a bone marrow aspirate, but peripheral blood can also be used. The most frequent karyotypic abnormalities in CLL are trisomy 12 and structural abnormalities of chromosomes 13 and 14.[3] The most common chromosomal aberration is 13q deletion and involves the rb-1 locus, a tumor suppressor gene that may have pathogenetic significance in CLL.[4] However, this abnormality is demonstrated only in a minority of cases.

Malignant lymphoma, leukemic phase

Leukemic transformation of malignant lymphoma is a well recognized entity. For many years, this condition was termed lymphosarcoma cell leukemia (LSCL) and dates from a period when lymphosarcoma, reticulum cell sarcoma, and Hodgkin's disease were the only known forms of malignant lymphoma. Despite its archaic, controversial, and imprecise nature, the term LSCL has endured and is presently found in most standard hematology textbooks. This term, however, should be discontinued and replaced by "malignant lymphoma, leukemic phase (MLLP)" to designate the leukemic stage of any non-Hodgkin's lymphoma in which tumor cells exceed the absolute normal lymphocyte count.[5]

Because more than 80% of non-Hodgkin's lymphomas originate from clonal proliferations of B-lymphocytes, it is apparent why most examples of MLLP are of B-phenotype. Moreover, because small-cleaved follicular lymphoma is the most prevalent form of non-Hodgkin's lymphoma, it becomes clear why the "lymphosarcoma" cell is frequently depicted in literature as a small cleaved lymphocyte. Less frequently, mantle cell lymphoma converts to a leukemic phase.

Incidence and prognosis. Using Sensitive fluorescent activated cell sorter analysis, up to 80% of patients with non-Hodgkin's lymphoma can be shown to have a monoclonal B-cell population in the blood.[6] The presence of circulating small cell lymphoma cells does not impart a poorer prognosis but does correlate with the extent of dissemination, as 90% of Ann Arbor stage III and IV have circulating lymphoma cells. However, development of leukemic phase with diffuse large cell lymphoma is ominous and associated with an aggressive course. Fortunately, the incidence is much less for large cell than for small cleaved cell lymphoma.

Blood and immunophenotypic findings. The importance of recognizing MLLP lies in not confusing this with acute lymphoblastic leukemia (ALL) or CLL. In ALL, blast forms have immature chromatin and are nucleolated. The chromatin of CLL cells are coarser and more mature. However, there are cases which are difficult to distinguish solely on morphologic features, and flow cytometry is usually required to help separate these entities. Typically, small cleaved cell lymphoma cells have strong (or bright) surface immunoglobulin (slg) expression, CD10 and CD20 positivity, and lack CD5 expression. Mantle cell lymphoma has a phenotype closely related to CLL but tends not to express CD23, and has moderate expression of surface immunoglobulin.

Because all forms of non-Hodgkin's lymphoma, including newly recognized entities such as monocytoid B-cell lymphoma and anaplastic large cell lymphoma (Ki-1 positive) can have circulating lymphoma cells, it is imperative to correlate appearances of circulating lymphoma cells with those of the lymph node biopsy, bone marrow biopsy, and with all available immunophenotypic and clinical data.

Hairy cell leukemia

Most cases of HCL present with pancytopenia, splenomegaly, and a dry bone marrow tap. In rare instances, pathologic examination of the spleen following removal due to trauma has incidentally revealed HCL.

This unusual form of chronic leukemia was first described by Bouroncie in 1958 and is readily diagnosed by examination of the blood and bone marrow.[7] Pancytopenia is present in more than 50% of cases, and splenomegaly is present at the initial diagnosis in at least 80% of cases. Moderate normocytic and normochromic anemia is usually evident, and thrombocytopenia and leukopenia is present in 70% of cases. Monocytopenia is invariably demonstrable, and neutropenia is present in most cases.

Blood findings. Hairy cells are observed in the peripheral blood in 90% of HCL patients. However, a leukemic presentation with hairy cells greater than 5000/[micro]L is seen in less than 20% of patients. In well prepared Wright-Giemsa-stained preparations, hairy cells reveal a round or oval, centrally or eccentrically placed nucleus with evenly distributed lacy chromatin and one or two inconspicuous nucleoli. The cytoplasm of hairy cells is generally pale blue, abundant, and ruffled. Rarely, rod-shaped inclusions correlate with ribosome-lamella complexes in the cytoplasm.

Cytochemical stains: Tartrate-resistant acid phosphatase stain. Because the irregularity of cell membranes may be observed in other lymphoproliferative disorders or may result from artifact, the application of the tartrate-resistant acid phosphatase (TRAP) stain in HCL has a critical role. However, some variation in activity and staining intensity after treatment is to be expected. In about 5% of cases of untreated HCL, no TRAP activity is found. Since TRAP activity has been observed in some cases of CLL, MLLP, Sezary syndrome/mycosis fungoides (SS/MF), adult T-cell lymphoma leukemia (ATLL), Waldenstrom's macroglobulinemia (WM), PLL, and some cases of non-lymphoid leukemia, clinicopathologic correlation is invaluable. To enable accurate determination of TRAP activity, fresh smears should be evaluated.

Marrow findings. Although the aspirate in HCL is often dry secondary to reticulin fibrosis, hairy cells can be readily identified on touch preparations of the biopsy. Focal or diffuse involvement of the bone marrow biopsy is the rule, and appearances are characteristically monomorphic. Tumor cells are lymphocytoid, and reveal abundant clear cytoplasm. Hairy ruffles are not seen in the biopsy. Other hematopoietic elements are usually decreased. Pericellular reticulin fibrosis is common.

Immunophenotypic analysis. Hairy cells will often demonstrate bright CD22 and CD11c co-expression and segregate out as a distinct population on two-color flow cytometric analysis. Hairy cells are also characteristically CD11c, CD19, CD20, CD22, CD25, CD103, and variably CD38 positive.

Detection of minimal residual disease. Following the introduction of 2-chlorodeoxyadenosine (2-CDA) for the treatment of HCL, the role of therapeutic splenectomy has decreased, and after a single cycle of 2-CDA, the tumor burden in the bone marrow may be reduced to remission patterns.[8] To enable evaluation of specimens with a low tumor burden, bone marrow biopsies are stained with L-26, a B-call marker that works well in decalcified bone marrow biopsies.[9] CD3 immunostaining should also be included to assess normal background levels of lymphocytes in biopsy specimens.

Chromosomal abnormalities. No specific chromosomal abnormality is present in HCL, and cytogenetics are not submitted in most cases.

Large granular lymphocytic leukemia

Large, granular lymphocytic (LGL) leukemia is a rare but distinct leukemic disorder within the spectrum of post-thymic T-cell neoplasia and is characterized by persistent lymphocytosis and neutropenia. Although LGL leukemia is the term generally preferred, a plethora of synonyms have been used to designate the manifestations of this disease, ranging from "an indolent and possible reactive disorder of immune regulation" to "an aggressive malignancy."

Most patients with LGL leukemia are older than 50 years of age. However, pediatric cases have been reported. About 25% of patients are asymptomatic and diagnosed incidentally during examination of the complete blood count and peripheral smear results. Chronic recurrent infections with neutropenia often serve as a clue to the diagnosis.

The lymphocytes in LGL leukemia were originally designated T-gamma (suppressor) cells, because they uniformly expressed Fc receptors for immunoglobulin G (IgG) (CD16) by rosetting techniques. Subsequent immunophenotyping studies have divided LGL leukemias into two discrete subsets: T-cell LGL, which tests positive for CD2 (CD2+), CD3, (CD3+), CD8 (CD8+), and CD16 (CD16+); and natural killer-LGL (NK-LGL), which tests positive for CD2 and CD16, and tests negative for CD3 (CD3-) and CD8 (CD8-). These subsets differ in clinical presentation, course and prognosis.[10-12]

T-cell LGL leukemia. T-cell LGL leukemia is an indolent, chronic, relapsing disorder of mid-life dominated by recurrent infections, fluctuating neutropenia, and mild rheumatoid arthritis. Most patients have splenomegaly and may therefore be considered to have Felty's syndrome. Most T-cell LGL leukemia patients have only a moderate lymphocytosis (median 7,800/[micro]L), but the numbers of LGLs in the blood are 20 times higher than normal (median 4,200/[micro]L versus normal median of 220 LGLs). Higher counts have been reported especially following splenectomy.

The lymphocytes in T-LGL leukemia are mostly granular. However, the degree and size of granules is variable. Nucleoli and immaturity of chrometin are absent. Most cytoplasmic granules of LGL are microtubular ultrastinctures of unknown significance and are designated parallel tubular arrays. Neutropenia is present in 80% of cases and is subject to cyclic changes, which, at their lowest point, can border on agranulocytosis. The mechanism of the neutropenia has been related to antineutrophil antibodies or circulating immune complexes. Indeed, these patients are often subject to complications of autoimmune disorders such as defective cell-mediated immunity (CMI), thrombocytopenia, and pure red cell aplasia. Evaluation of the bone marrow usually demonstrates a diffuse infiltration indistinguishable by light microscopy from other low-grade lymphoproliferative disorders. Despite its indolent clinical course, T-cell LGL is a clonal disease as defined by cytogenetic criteria and T-cell receptor (TCR) gene rearrangements. Treatment is generally aimed at controlling infections. However, chemotherapy may be indicated in patients with "B" symptoms (fever, night sweats, weight loss), that is, a more aggressive clinical course.

Natural killer LGL leukemia. Natural killer LGL leukemia is less common, occurs at a younger age, and is associated with rapid dissemination, multiorgan failure, and resistance to chemotherapeutic intervention. Patients usually die within months, although bone marrow transplantation may salvage some if implemented early. The morphologic appearance of lymphocytes in NK-LGL leukemic cells is indistinguishable from T-cell LGL leukemic cells. The usual immunophenotypic profile is CD2+, CD3-, CD16+, CD56+, but there is considerable diversity reported.

The differential diagnosis of LGL leukemia includes reactive lymphocytosis, some cases of Felty's syndrome, CLL, T-PLL, HCL, and MLLP. In evaluating cases of lymphocytosis for LGL leukemia, we find that a profile of CD3-, CD16+, and CD56+ LGL without neutropenia is more supportive of NK cell hyperplasia than Tcell LGL or NK-LGL leukemia.

Prolymphocytic leukemia

In 1963, Galton proposed the concept of PLL as an unusual variant of CLL.[13] Each year in the United States, between 60-100 new cases of PLL are diagnosed. The relative frequency of PLL to CLL is about 1:9. Greater than 50% of patients with PLL are older than 70 years of age, and the ratio of T:B phenotype is around 1:3.

PLL usually manifests with massive splenomegaly, hyperleukocytosis, bone marrow infiltration, and minimal adenopathy. T-cell PLL is a more aggressive disease and has a higher incidence of adenopathy, leukocytosis, skin infiltration, and hepatomegaly. However, splenomegaly is more frequent in B-cell PLL, and may not always be massive. Hyperleukocytosis with counts greater than 100.0 x [10.sup.9]/L are present in 65% of patients, and may result in fatal microvascular obstruction.

Blood findings. Leukemic cells of PLL are larger than either normal or CLL cells. However, a small cell variant of PLL is described. Both cell types may coexist in any given patient. No pathognomonic cytologic differences between T-cell PLL and B-cell PLL exist, and the most characteristic feature of PLL is a large nucleus. The nuclei of B-cell PLL are usually round or oval, and occasionally clefted superficially. Eccentric localization of nuclei in some instances may be reminiscent of WM. In contrast, the nuclei of T-cell PLL may be irregular, folded, or clefted. No pathognomonic cytoplasmic features are present in PLL. However, in T-cell PLL the alpha-naphthyl acetate esterase (A-EST) reveals a bold, focal reaction pattern characteristic of T-cells. The TRAP stain may be positive, but immunologic studies usually clearly separate this disorder from HCL. It should be emphasized that one must examine well-stained and spread peripheral smear preparations to appreciate the cytologic features described above. For example, drying artifact can result in shrinkage and result in prolymphocytes resembling CLL cells.

Marrow findings. The patterns of bone marrow are variable and include nodular, interstitial, diffuse, and mixed patterns. Purely nodular patterns are rare and more commonly seen in CLL. Typically, there is gradual replacement of hematopoietic elements from encroaching leukemic cells in PLL.

Immunophenotypic analysis. Flow cytometry can help separate PLL from CLL and divide them into B-cell and Tcell phenotypes. B-PLL demonstrates strong (or bright) surface immunoglobulin, human leukocyte antigen-DR (HLA-DR) positivity, variable to absent CD5, moderate to bright CD20, and negative CD10 expression. The antibody FMC7 is reported to be expressed in prolymphocytes and not CLL lymphocytes and is utilized as a marker of prolymphocytic transformation. However, our experience is that FMC7 expression is much less reliable than morphology in identifying prolymphocytes. Because Tcell PLL is a post-thymic neoplasm, the cells are TdT negative. Greater than 90% of T-cell PLL cases are CD7+. About 70% are CD4+/CD8-, 11% are CD4-/CD8+, and 20% express both CD4 and CD8 antigens. In certain instances, patients with CD4 activity have done better than those who are CD8+.

Chromosomal abnormalities. Cytogenetic changes are more easily demonstrated in PLL. In B-cell PLL, the most common abnormality is a marker chromosome 14q+.[14] Although the donor chromosome responsible for the marker is unknown in many cases, in some it results from a t(11;14) transassociation, which may be found in other B-cell growth disorders. Cytogenetic abnormalities in T-cell PLL include inv[14], trisomy 8q, 6q- and trisomy 7q.[15] The inversion involving 14q11 breakpoint, where the gene coding for the alpha chains of the alpha-beta TCR is located, and at 14q32, which is located in the proximity of the immunoglobulin heavy (IgH) chain gene, appears characteristic but not entirely unique to patients with T-PLL, and only rarely is observed in other mature T-cell leukemias.[16] It is apparent, therefore, that the different karyotypic patterns of these phenotypic variants of PLL reflect fundamental differences and are useful in distinguishing BPLL from T-PLL.

Differential diagnosis. The differential diagnosis of PLL includes the prolymphocytic transformation of CLL, HCL, WM, MLLP, plasma cell leukemia (PCL), SS, and ATLL. Prolymphocytic transformation occurs in patients with a history of CLL, refers to increasing numbers of circulating prolymphocytes, and is usually accompanied by increasing white cell counts, increasing splenomegaly, unresponsiveness to therapy, and short survival. Separation of PLL from the other chronic lymphold leukemias can be made on the basis of clinical, morphologic, immunophenotypic, and cytogenetic studies as previously discussed.

Plasma cell leukemia

In 2-3% of patients with advanced multiple myeloma (MM), plasma cells spill into the circulation, and when their absolute number increases above 2,000/[micro]L or exceeds 20% of the total white cell count, a diagnosis of PCL is permissible.[16] In some patients with MM, a leukemoid type reaction will develop - a situation that indicates terminal progression of their disease. Occasionally, PCL may be found in a patient without a previously established history of multiple myeloma. Most patients will have multiple myeloma that has gone unrecognized and will have a course similar to patients with advanced stage myeloma. However, a primary form of PCL is described but has a more aggressive clinical course. Such cases are rare (fewer than 1 in 1 million) and present with fulminant leukemia, rapid replacement of the marrow by immature plasma cells, hepatosplenomegaly, severe anemia, and bleeding manifestations.

Blood findings, In most patients with PCL, the total leukocyte count usually varies between 20-100 x [10.sup.9]/L. However, counts as high as 270 x [10.sup.9]/L have been reported. Plasma cells in the peripheral blood may reveal a range of cytological appearances varying between those of well developed plasma cells with eccentric nuclei, clumped chromatin, radially oriented parachromatin, a distinct perinuclear hof and abundant cytoplasm; to those with lymphoplasmatic features, a high nuclear/cytoplasmic ratio, prominent nuclei, and biastic appearances virtually indistinguishable from other acute leukemias. Rouleaux formation, increased erythrocyte sedimentation rate, thrombocytopenia, and anemia may be evident.

Marrow findings. The bone marrow in PCL is often diffusely involved, and other hematopoietic elements are usually decreased. Flame cells, intracytoplasmic crystals, and Dutcher bodies may be present. Myelofibrosis is usually absent, and osteoporosis is variably present. Light chain restriction is characteristically present, and readily demonstrable by the immunoperoxidase techniques. Leukemic cells frequently test negative for CD5, CD10, CD19, and CD20, and positive for CD38. See Table 2 for other differentiating immunophenotypic features between PCL, B-cell PLL, and CLL.

The relative incidence of different classes of immunoglobulins in PCL is similar to that of multiple myeloma, except immunoglobuin E (IgE) is greatly overrepresented. Incomplete immunoglobulin molecules or no immunoglobulin production may be observed. The cause of PCL in over 25% of patients with lgE multiple myeloma, the rarest of all myelomas, is presently unknown.[18]

Patients with PCL may have severe paraprotein-related problems such as hyperviscosity, cryoglobulinemia, abnormal platelet function, and bleeding. Primary PCL, unlike PCL secondary to MM, tends to respond well, if briefly, to conventional MM therapy. Survival in the range of 2 to 4 years has been reported in these patients.[19,20]
Table 2

Differentiating immunophenotypic features between PCL, B-PLL, and

parameter PCL B-PLL CLL

slg - +++ +/-
clg +++ +/- +/-
CD5 - +/- +++
CD10 - -/+ -
CD19/20 - +/+ +
CD23 +/- -/+ +++
CD25 - - +/-
CD38 + - -
FMC7 +/- +++ -/+

Adult T-cell lymphoma-leukemia

When first described in 1977, ATLL appeared to be confined to southwestern region of Japan.[21] Subsequently, cases have been reported from the Caribbean basin, the southeastern region of the United States, and parts of South America, Africa, and Italy. Although suspected to be caused by an oncogenic virus, it was not until 1980 that the first isolates of human T-cell lymphotrophic virus (HTLV-I) were recovered from patients with this disorder.[22] ATLL is the only chronic human leukemia where the virus has been demonstrated in tissue culture in virtually 100% of cases. Although ATLL is caused by HTLV-I, not all persons with antibodies against HTLV-I have ATLL. In Japan, up to 26% of healthy persons are antibody positive, thus attesting to the widespread prevalence of infection.[23,24] Vital transmission is believed to follow sexual or other intimate contact, blood transfusion, intrauterine infection, or through the mother's milk. The latent period between infection and the development of ATLL is believed to be 20-30 years.

Blood findings. ATLL typically manifests in the adult, and acute, chronic, and smoldering forms are recognized.[24] Patients frequently present with skin lesions, adenopathy, hepatosplenomegaly, and hypercalcemia. The peripheral blood is involved in greater than 65% of patients at initial presentation, and leukemic features develop in almost all cases. Initially, only a few ATLL cells may be observed in the peripheral blood. Nevertheless, counts as high as 500,000/[micro]L have been recorded. ATLL cells reveal highly convoluted nuclei with deep multilobulated indentations (flower-shaped cells). The cell size and nuclear/cytoplasmic (N/C) ratio is larger than that of normal lymphocytes.

Morphologic findings. In bone marrow aspirates, ATLL cells appear similar to those observed in the peripheral blood. The bone marrow biopsy will confirm the presence of infiltrates, and additionally, evidence of bony remodeling and fibrosis may develop.

Lymph node biopsies reveal a variable pattern of involvement, and small, mixed, and large cell forms of ATLL have been described. Appearances are often difficult to categorize into' current classification schemes. Skin lesions may reveal Pautrier's epidermal abscesses. In this event, morphological appearances may not be readily distinguished from those of MF/SS.

Immunophenotypic findings. ATLL cells in most cases are CD4+ and TdT-. CD8 activity has been variable; however, most cases express high levels of the interleukin-2 (IL-2) receptor, CD25. Not only can this antiden be utilized in immunophenotyping, but it is also being exploited as a marker for hew therapeutic modalities.

Chromosomal abnormalities. Chromosomal abnormalities are frequent, and PCR analysis reveals rearrangement of the TCR genes. Recent molecular findings have shown that the HTLV virus encodes for transregulatory proteins that affect vital gene expression and appear to have a role in transformation.[26]

Sezary syndrore/mycosis fungoides

Previously considered a skin disease, SS and its localized form, MF, are established examples of a T-cell neoplasm. Each year, about 1,000 new cases are diagnosed in the U.S. Patients with SS/MF develop scaly, pruritic skin lesions, which may manifest as patchy infiltrates, plaques or tumors, and may go on to ulcerate. Rarely, cutaneous tumors (form d'emblee) are the initial manifestation.

In the early stages of MF, circulating SS/MF cells may be absent in the peripheral blood. In contrast, patients with SS have generalized erythroderma, and circulating SS/MF cells are frequently present. Some overlap of clinical and laboratory findings may occur, making differentiation of these related disorders difficult.

Blood findings. Identifying Sezary cells in the peripheral blood remains a dilemma for many clinicians. SS/MF cells occur in two forms, and both small and large cell variants may be simultaneously observed in a peripheral blood film. On direct cytological examination, Sezary cells reveal a highly convoluted, fissured, grooved, and often cerebriform nucleus. No pathognomonic cytoplasmic changes exist. Absolute cell counts seldom exceed 20.0 x [10.sup.9]/L. However, higher counts have been reported.

Morphologic findings. The bone marrow may be involved in 20% of patients at diagnosis and involvement may have prognostic implications.[27,28] Lesions in the bone marrow biopsy may be identified, and are seldom, if ever, observed in the aspirate.

Interpretation of the lymph node biopsy in SS/MF has remained controversial, and although late stage lesions may be readily interpreted by the casual observer, the diagnosis of earlier lesions is more difficult and may require correlative examination of immunostains, particularly those for CD3, L-26, and S-100. In cases of suspicious lymph node involvement, searching for clonal TCR gene rearrangements and utilizing molecular genetic analysis may help in a resolution.

Skin biopsies from patients with SS/MF often reveal epidermal Pautrier's microabscesses, and are often accompanied by an atypical dermal lymphoid infiltrate.

Immunophenotypic findings. SS/MF cells are CD4+ and are CD8- and TdT-. It is generally agreed that the normal T- to B-lymphocyte ratio in the peripheral blood is about 4:1, and the CD4 to CD8 ratio is about 2:1. With increasing numbers of CD4+ cells as in SS/MF, this ratio is altered.

Chromosomal abnormalities. No consistent cytogenetic abnormality has been identified in SS/MF. Random abnormalities are frequent. Recent studies have suggested a role for HTLV (human T-cell leukemia/lymphoma virus) in cutaneous T-cell lymphomas.[29] Combined PCR and Southern blot analysis identified the presence of HTLV proviral sequences in more than 90% of patients with SS/MF. Viral particles have also been identified by immunoelectron microscopy. However, other studies have failed to confirm these results.[30]

In an upcoming issue, the authors will review chronic leukemias of myeloid origin.

Objectives of this article:

1. Differentiate morphologic characteristics of chronic leukemias of lymphoid origin.

2. Identify cell markers distinguished by flow cytometry.

3. Identify clinical findings of chronic lympoid leukemias.

CE test published through an educational grant from

Table 1

Chronic leukemias

Chronic leukemias of lymphoid origin

Chronic lymphocytic leukemia Malignant lymphoma, leukemic phase Hairy cell leukemia Large granular lymphocytic leukemia Prolymphocytic leukemia Plasma cell leukemia Adult T-cell lymphoma-leukemia Mycosis fungoides/Sezary syndrome

Chronic leukemias of myeloid origin

Chronic myelogenous leukemia Chronic myelomonocytic leukemia Mast cell leukemia Chronic monocytic leukemia Chronic neutrophilic leukemia Chronic eosinophilic leukemia


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James T. Rector is head of hematopathology at the National Naval Medical Center in Bethesda, MD. Harold R. Schumacher is head of hematopathology and professor of pathology at the University of Cincinnati Medical Center in Cincinnati, OH. James D. Cotelingam is head of hematology and clinical laboratories and professor of pathology at Louisiana State University Medical Center in Shreveport, LA.
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Author:Rector, James T.; Schumacher, Harold R.; Cotelingam, James D.
Publication:Medical Laboratory Observer
Date:Nov 1, 1998
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