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Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia

Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia
Literature review current through: Jan 2024.
This topic last updated: Apr 25, 2022.

INTRODUCTION — T cell prolymphocytic leukemia (T-PLL) is a rare, clinically aggressive T cell neoplasm composed of lymphoid cells, typically with involvement of the peripheral blood, bone marrow, lymph nodes, and spleen. The name "prolymphocyte" is a misnomer, as the tumor cells in this disease are of post-thymic T cell origin. This class of neoplasms includes many cases previously classified as T cell chronic lymphocytic leukemia, a category no longer included in the current World Health Organization classification.

The epidemiology, clinical presentation, pathology, and diagnosis of T-PLL are discussed here. The treatment and prognosis of T-PLL are presented separately. (See "Treatment of T cell prolymphocytic leukemia".)

EPIDEMIOLOGY — T-PLL is an extremely rare disease, comprising approximately 2 percent of mature lymphocytic leukemias in adults [1-3]. Sporadic T-PLL mainly affects older adults with a mean age at presentation of 63 to 65 years [4,5]. It has not been definitively reported in children or young adults. There is a slight male predominance with a male:female ratio of 1.33 [2].

Patients with ataxia telangiectasia have a greatly increased incidence of T-PLL with a different epidemiologic profile [6]. In contrast to patients with sporadic T-PLL, the median age of onset of T-PLL in patients with ataxia telangiectasia is about 30 years, and some cases appear in adolescence [7]. (See "Ataxia-telangiectasia".)

CLINICAL FEATURES — T-PLL is a clinically aggressive disease. Given its rarity, there is uncertainty regarding the frequency of various clinical and laboratory findings at diagnosis. Most patients present with an elevated white blood count (typically >100,000/microL).

On examination, hepatosplenomegaly (75 percent) and generalized lymphadenopathy (50 percent) are common; anemia (36 percent) and thrombocytopenia (51 percent) can be seen but are less common than in B cell prolymphocytic leukemia [2,5]. In addition, skin infiltration and serous effusions (eg, pleural, peritoneal) occur in approximately 25 and 15 percent of patients, respectively. Peripheral, periorbital, and conjunctival edema are also seen. Involvement of the central nervous system is rare. Systemic B symptoms (unexplained fevers/chills, night sweats, weight loss) are uncommon at the time of diagnosis but can develop as the disease progresses.

Approximately 15 to 20 percent of patients will be entirely asymptomatic at the time of diagnosis and have disease that remains stable or progresses slowly over years [8,9]. This clinical presentation has been termed "inactive T-PLL." Such patients have been diagnosed at an earlier period in their disease and the disease tempo will increase over time to "active T-PLL."

Testing for human T lymphotropic virus (HTLV) types 1 or 2 is negative.

PATHOLOGY

Morphology

Peripheral blood and bone marrow — Examination of the peripheral blood demonstrates a predominance of lymphoid cells (picture 1A-B). There are three morphologic variants [1,2,10]:

Typical (75 percent) – The tumor cells are medium-sized lymphoid cells with moderately condensed chromatin and a visible nucleolus. The nucleus can be round or oval. The cytoplasm is usually moderately abundant and slightly basophilic without granules. Cytoplasmic protrusions (blebs) are common.

Small cell variant (20 percent) – The tumor cells are small with condensed chromatin and a small nucleolus visible only by electron microscopy.

Cerebriform (Sézary cell-like) variant (5 percent) – The tumor cells have a very irregular nuclear outline resembling the cerebriform nucleus of Sézary cells seen in Sézary syndrome.

The bone marrow is infiltrated in an interstitial pattern by cells with similar morphology.

Skin — Skin infiltrations most commonly involve the trunk or the limbs and produce an erythematous maculopapular rash; nodular skin involvement may also be seen. T-PLL may also involve the face, where it manifests as purpura and edema, often in a periorbital distribution (picture 2) [11,12]. Skin biopsy of affected areas demonstrates perivascular or diffuse dermal infiltrates, sometimes with accompanying hemorrhage, but without epidermotropism.

Other tissues — The spleen demonstrates dense lymphoid infiltrates in the red pulp that often invade the splenic capsule. The white pulp is usually atrophied. Lymph node involvement is diffuse, often with prominent high-endothelial venules. Infiltration typically involves the paracortical areas and may spare the follicles.

Immunophenotype — T-PLL cells express CD52 (strongly) and pan-T cell markers (CD2, CD3, and CD7) (figure 1) [1]. Terminal deoxynucleotidyl transferase (TdT) is not expressed. CD3 may be expressed on the cell membrane at low or high levels. Expression of CD4 and CD8 is variable: 60 percent of cases are CD4+/CD8-, 25 percent of cases are CD4+/CD8+, and 15 percent of cases are CD4-/CD8+. The coexpression of CD4 and CD8 is practically unique to T-PLL among post-thymic T cell malignancies. T-PLL cells overexpress the oncogene TCL1 as demonstrated by immunohistochemistry and by flow cytometry.

Genetic features — T cell receptor genes are clonally rearranged. Chromosomal abnormalities are common, and 70 to 80 percent of cases have complex karyotypes [13]. One of the following rearrangements involving a member of the T cell leukemia/lymphoma 1 family of genes (TCL1A, TCL1B, or MTCP1) is seen in over 90 percent of cases, and each is relatively specific for T-PLL [1,6,13-16]:

inv(14)(q11q32)

t(14;14)(q11;q32)

t(X;14)(q28;q11)

These rearrangements involve either TCL1 at 14q32.13 or MTCP1 (a homolog of TCL1) at Xq28. They lead to aberrant expression of the TCL1 or MTCP1 proteins, which can be detected by immunohistochemistry or flow cytometry (at some centers). Fluorescence in situ hybridization (FISH) and immunohistochemistry (to detect aberrant protein expression) are more sensitive than cytogenetics for the detection of these abnormalities [17].

Additional chromosomal or genetic abnormalities, which are not specific to T-PLL but help to support the diagnosis include [8]:

Abnormalities in chromosome 8 (70 to 80 percent of cases) including isodicentric 8p11, t(8;8), and trisomy 8q [15,18].

Deletions or missense mutations involving the ataxia telangiectasia mutated (ATM) locus 11q23 (65 percent) [18-20].

Abnormalities in chromosomes 5, 12, 13, or 22; or a complex karyotype [13,21].

Haploinsufficiency for the CDKN1B tumor suppressor gene at 12p13 is found in approximately 50 percent of cases [13]. Other common findings include activating mutations in the JAK1 (1p31.3) or JAK3 (19p13.11) non-receptor tyrosine kinases (34 to 38 percent), abnormalities in chromosome 6 (33 percent) and chromosome 17 (26 percent), and deletion of the TP53 gene at 17p13 (50 percent) [6,18,21-24].

A subset of cases also have been reported to have mutations in STAT5B, the small GTP-binding protein RHOA, and the epigenetic regulators EZH2, TET2, and BCOR, none of which are specific for T-PLL [25].

EVALUATION AND DIAGNOSIS

Evaluation — The diagnosis of T-PLL should be suspected in an adult found to have an absolute lymphocytosis, often with few additional symptoms. Evaluation of such patients should include [8]:

A complete blood count with differential

Examination of the peripheral smear

Flow cytometry and immunostains to determine the immunophenotype of the circulating lymphocytes in the peripheral blood, and to test for aberrant TCL1 and MTCP1 expression

T cell receptor analysis of the circulating lymphocytes (with polymerase chain reaction [PCR] or next-generation sequencing)

Testing for human T lymphotropic virus (HTLV) type 1 (to exclude adult T cell leukemia-lymphoma)

Karyotyping

Fluorescence in situ hybridization to look for rearrangements involving TCL1 and MTCP1

Evaluation of the bone marrow is not usually necessary but is included in the evaluation of patients with unexplained cytopenias or diagnostic uncertainty. The urgency of evaluation is guided by the patient's clinical condition. Most patients are clinically stable and can be evaluated, diagnosed, and managed as outpatients. Rarely, patients will present with complications secondary to rapid disease progression and require hospitalization for stabilization and diagnostic evaluation.

Diagnostic criteria — Based on the evaluation above, T-PLL can be diagnosed using the following major and minor criteria proposed by The T-PLL International Study Group (TPLL-ISG) [8]:

Major criteria

Cells with T-PLL phenotype in peripheral blood or bone marrow >5000/microL (5 x 109/L)

Clonality of the T lymphocytes by PCR for T cell receptor rearrangement or by flow cytometry

Abnormalities of 14q32 or Xq28, or expression of TCL1 or MTCP1

Minor criteria

Abnormalities involving chromosome 11 (11q22.3; ATM)

Abnormalities in chromosome 8: idic(8)(p11), t(8;8), trisomy 8q

Abnormalities in chromosome 5, 12, 13, 22, or complex karyotype

Involvement of T-PLL specific site (eg, splenomegaly, effusions)

The diagnosis of T-PLL requires all three major criteria, or fulfillment of the first two major criteria plus one minor criterion. All cases of T-PLL meet the first two major criteria, and the third major criterion is present in more than 90 percent of cases. The remainder of cases can be captured using the minor criteria and are collectively referred to as "TCL1-family negative T-PLL."

As described above, the typical T-PLL phenotype includes expression of CD52 and the pan-T cell markers CD2, CD3, and CD7; surface expression of CD3 is absent in about one-third of cases, but CD3 is present in the cytoplasm of the tumor cells in such cases. Expression of CD4 and CD8 vary. Serologic and PCR testing for HTLV type I is negative thereby ruling out adult T cell leukemia-lymphoma.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of T-PLL includes other chronic lymphoid neoplasms or T cell neoplasms with a leukemic presentation. The main entities are described in more detail below, and a broader differential is included in the table (table 1).

B cell prolymphocytic leukemia — B cell prolymphocytic leukemia (B-PLL) has a similar clinical presentation and morphologic appearance to T-PLL. Skin infiltration and lymphadenopathy, which are unusual in B-PLL, are much more common in T-PLL. These two entities differ in their immunophenotype. Unlike T-PLL, B-PLL expresses one or more B cell antigens (CD20, CD22, FMC7, CD79a) and lacks T cell antigens. (See "B cell prolymphocytic leukemia".)

Mycosis fungoides/Sézary syndrome — Both T-PLL and mycosis fungoides (MF) are T cell neoplasms that can involve the blood and skin. The morphology of the "cerebriform" (Sézary cell-like) variant seen in 5 percent of patients with T-PLL resembles the Sézary cells that are prominent in Sézary syndrome and often seen in low numbers in MF. MF is diagnosed using an algorithm that incorporates clinical features, histology, immunophenotype, and molecular biology in a point-based system (table 2). A diagnosis of MF is made when a total of four points or more is determined. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Chronic lymphocytic leukemia — Both T-PLL and chronic lymphocytic leukemia (CLL) can present with lymphocytosis and splenomegaly and have circulating prolymphocytes in the blood.

Typical CLL cells are small, mature-appearing lymphocytes with a dense nucleus, partially aggregated chromatin, and without discernible nucleoli. There is a narrow border of pale or slightly basophilic cytoplasm (picture 3). Prolymphocytes usually comprise fewer than 10 percent of the circulating cells. Most importantly, CLL is a B cell neoplasm and demonstrates both expression of B cell-associated antigens (CD19, CD20, and CD23) and the T cell-associated antigen CD5. T-PLL does not express B cell-associated antigens. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Adult T cell leukemia-lymphoma — Adult T cell leukemia-lymphoma (ATL) is a peripheral T cell neoplasm associated with infection by the human T-lymphotropic virus, type I (HTLV-I). Serologic and polymerase chain reaction (PCR) testing for HTLV-I is used to exclude this diagnosis. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

Hairy cell leukemia and hairy cell leukemia variant — The cytoplasm of T-PLL can demonstrate cytoplasmic protrusions or blebs that may resemble the projections seen in the circulating tumor cells of hairy cell leukemia (HCL) and hairy cell leukemia variant (HCLv). Hairy cells strongly express pan-B cell antigens (CD19, CD20, CD22) and usually lack expression of CD5, CD10, CD21, and CD23. Hairy cells also characteristically express CD11c, CD25, CD103, CD123, cyclin D1, and annexin A1. HCLv is more likely to have a morphology that is reminiscent of T-PLL, including intermediate-sized cells with nucleoli and irregular nuclear contours, but is easily distinguished from T-PLL by immunophenotyping, which reveals expression of B cell markers (CD19, CD20, CD22) and the absence of T cell markers. (See "Clinical features and diagnosis of hairy cell leukemia".)

T cell large granular lymphocyte leukemia — Both T-PLL and T cell large granular lymphocyte (LGL) leukemia can present with a peripheral blood lymphocytosis, although in T-LGL this is rarely high. The tumor cells of LGL leukemia are characterized by their large size (15 to 18 microns), abundant cytoplasm containing typical azurophilic granules, a reniform or round nucleus, and a mature post-thymic immunophenotype. They express CD8 and CD57 with or without the expression of CD16 and the natural killer cell marker CD56 (algorithm 1). (See "Treatment of large granular lymphocyte leukemia".)

SUMMARY

Clinical presentation – T cell prolymphocytic leukemia (T-PLL) is a rare T cell neoplasm comprised of lymphoid cells, typically with involvement of the peripheral blood, bone marrow, and spleen. It is most common in older adults. (See 'Epidemiology' above.)

Patients typically present with an elevated white blood count (usually >100,000/microL), often with few other symptoms. On examination, hepatosplenomegaly and generalized lymphadenopathy are common. Anemia, thrombocytopenia, skin infiltration, and serous effusions can be seen but are less common. (See 'Clinical features' above.)

Diagnostic evaluation – Evaluation of suspected cases should include examination of the peripheral blood coupled with immunostains, flow cytometry, and cytogenetic studies. Evaluation of the bone marrow is not usually necessary but is included in the evaluation of patients with unexplained cytopenias or diagnostic uncertainty. (See 'Evaluation' above.)

The peripheral blood will demonstrate >5000/microL (5 x 109/L) of cells with a T-PLL phenotype. Tumor cells express high levels of CD52 and also express pan-T cell markers (CD2, CD3, and CD7) and TCL1 or MTCP1. Abnormalities of 14q32 or Xq28 are characteristic. Serologic and polymerase chain reaction testing for human T-lymphotropic virus, type I, is negative. Criteria for diagnosis have been proposed by The T-PLL International Study Group (TPLL-ISG). (See 'Diagnostic criteria' above.)

Differential diagnosis – The differential diagnosis of T-PLL includes other lymphoid neoplasms with a leukemic presentation (table 1). (See 'Differential diagnosis' above.)

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