T-cell prolymphocytic leukemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2], Maria Fernanda Villarreal, M.D. [3]

Synonyms and keywords: T-cell chronic lymphocytic leukemia; "Knobby" type of T-cell leukemia; T-prolymphocytic leukemia/T-cell lymphocytic leukemia- Kiel; T-PLL

Overview

T-cell-prolymphocytic leukemia (also known as T-PLL) is a rare, mature T-cell leukemia with aggressive behavior and predilection for blood, bone marrow, lymph nodes, liver, spleen, and skin. T-cell prolymphocytic leukemia was first described by Catovsky in 1973. There is no classification system for T-cell prolymphocytic leukemia. The inversion of chromosome 14 (14q11) has been associated with the development of T-cell prolymphocytic leukemia. T-cell prolymphocytic leukemia is very rare, and it represents 2% of all small lymphocytic leukemias in adults. T-cell prolymphocytic leukemia is more commonly observed among young adult patients aged between 30 to 40 years old. Males are slightly more affected with are more commonly affected with T-cell prolymphocytic leukemia than females. Laboratory findings consistent with the diagnosis of T-cell prolymphocytic leukemia, include: high lymphocyte count (> 100 x 109/L), anemia, thrombocytopenia, and negative HTLV-1 serology. There are no specific imaging findings associated with T-cell prolymphocytic leukemia. Prognosis is generally poor, and the median survival time of patients with T-cell prolymphocytic leukemia is approximately 7 months. The mainstay of therapy for T-cell prolymphocytic leukemia is alemtuzumab (anti-CD52). However, T-cell prolymphocytic leukemia is often resistant to therapy. Autologous and allogeneic stem cell transplants is the mainstay of therapy for patients who achieve remission.

Historical Perspective

• 40 years ago, in 1973, Catovsky first described four cases of T-cell prolymphocytic leukemia.
• In 1994, Harris a pathologist from Boston and his colleagues made an effort to classify T-cell prolymphocytic leukemia.

Classification

• T-cell prolymphocytic leukemia classification is based on its morphology.

Morphological Variant	Percentage of total number
Typical T-cell prolymphocytic leukemia	75 percent
Small cell variant	20 percent
Cerebriform (Sézary cell-like) variant	5 percent

Pathophysiology

• T-cell prolymphocytic leukemia arises from mature (post-thymic) T-cell, which is normally involved in in cell-mediated immunity.
• The inversion of chromosome 14 (14q11) has been associated with the development of T-cell prolymphocytic leukemia.
• Patients with T-cell prolymphocytic leukemia have TCR gene rearrangements for the γ and δ chains.
• Mutations of chromosome 8 are seen in approximately 75% of patients.
• On gross pathology, characteristic findings of T-cell prolymphocytic leukemia, include:

• No remarkable findings

• On microscopic histopathological analysis, characteristic findings of T-cell prolymphocytic leukemia, include:

• The immunophenotype CD4+/CD8- (present in 60% of cases)
• The immunophenotype CD4+/CD8+ (present in 25%)

• The immunophenotype CD4-/CD8+ (15% of cases) Different variants of T-cell Lymphocytic leukemias can be differentiated based on microscopic and gross finding.

Morphological Variant	Gross Findings	Microscopic Findings
Typical T-cell prolymphocytic leukemia		Medium-sized lymphoid cells Densely packed chromatin Prominent nucleolus with blisters on surface
Small cell variant		Small cells Dense chromatin Minute electron microscopically visible nucleolus
Cerebriform (Sézary cell-like) variant		Asymmetrical nuclear outline Cerebriform nucleus

Immunophenotype

• T-cell prolymphocytic leukemia cells express different markers including:
  • CD52 (strongly)
  • Pan-T cell markers such as:
    • CD2
    • CD3 (might be low or high level)
    • CD7
  • Oncogene TCL1
  • CD4+/CD8- (present in 60% of cases)
  • CD4+/CD8+ (present in 25%, unique for T-cell prolymphocytic leukemia)
  • CD4-/CD8+ (15% of cases)
  • Negative terminal deoxynucleotidyl transferase (TdT)

Genetic

• There are many chromosomal abnormalities in T-cell prolymphocytic leukemia, which mostly involve chromosome 14. Different types of genetic abnormalities are as follows:
  • Inv(14)
  • t(14;14)(q11;q32)
  • t(X;14)(q28;q11) which involves a homolog of TCL1, MTCP1 (mature T cell proliferation 1 gene)
  • idic(8p11)
  • t(8;8)
  • Trisomy 8q
  • Del(12p13)
  • Abnormalities in chromosome 6
  • Abnormalities in chromosome 17
  • Deletion of TP53 gene
  • Deletions of or missense mutations at the ataxia telangiectasia mutated (ATM) locus 11q23

Pathophysiology

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Causes

• Common causes of T-cell prolymphocytic leukemia, include:

• Genetic mutations (e.g. Trisomy 8, chromosomal abnormalities)

Differentiating T-cell Prolymphocytic Leukemia from Other Diseases

• T-cell prolymphocytic leukemia must be differentiated from other diseases that cause lymphadenopathy, hepatomegaly, and fever, such as:

• Sézary syndrome
• Cutaneous T cell lymphoma
• Angioimmunoblastic T cell lymphoma
• B-cell prolymphocytic leukemia

Epidemiology and Demographics

• T-cell prolymphocytic leukemia is very rare, and it represents 2% of all small lymphocytic leukemias in adults.
• The incidence of T-cell prolymphocytic leukemia increases with age; the median age at diagnosis is 65 years.
• Patients with ataxia telangiectasia and T-cell prolymphocytic leukemia are young adults; the median age at diagnosis is 30 years.

• Males are slightly more affected with T-cell prolymphocytic leukemia than females.

• There is no racial predilection for T-cell prolymphocytic leukemia.

Risk Factors

• There are no risk factors associated with the development of T-cell prolymphocytic leukemia.

Screening

There is insufficient evidence to recommend routine screening for T-cell prolymphocytic leukemia.

Natural History, Complications and Prognosis

• The majority of patients with T-cell prolymphocytic leukemia are symptomatic at the time of diagnosis.
• Early clinical features include fever, fatigue, and lymphadenopathy.
• If left untreated, patients with T-cell prolymphocytic leukemia may progress to develop multiple organ failure.
• Common complications of T-cell prolymphocytic leukemia, include:

• Graft-versus-host disease (allogeneic transplant)
• Infections
• Bleeding

• Prognosis is generally poor, and the median survival time of patients with T-cell prolymphocytic leukemia is approximately one to two years.
• Patients with CD45RO+/CD45RA- immunophenotype tend to have a more indolent course.
• It seems following factors are associated with worse prognosis:
  • Increased expression of TCL1
  • Increased activity of the serine-threonine kinase AKT

Diagnosis

Diagnostic Study of Choice

• There are no established criteria for the diagnosis of T-cell prolymphocytic leukemia. Patients with T-cell prolymphocytic leukemia are diagnosed by clinical presentation, pathology evaluation of the peripheral blood and bone marrow. Flow cytometry and immunostains should be performed to diagnose a T cell immunophenotype.

History and Symptoms

• Symptoms of T-cell prolymphocytic leukemia may include the following:

• Fever
• Weight loss
• Night sweats

Physical Examination

• Patients with T-cell prolymphocytic leukemia usually appear pale and malnourished.
• Physical examination may be remarkable for:

• Hepatomegaly
• Splenomegaly
• Generalized lymphadenopathy
• Skin infiltration
• Serous effusions:
  • Pleural effusion
  • Peritoneal effusion
• Central nervous system involvement (very rare)

Laboratory Findings

• Laboratory findings consistent with the diagnosis of T-cell prolymphocytic leukemia, include:

• High lymphocyte count (> 100 x 109/L)
• Anemia
• Thrombocytopenia
• Negative human T lymphotropic virus (HTLV) serology
• Peripheral Blood Smear demonstrated predominance of lymphocytes:
  • Typical variant:
    • Medium-sized lymphocytes
    • Condensed chromatin and a visible nucleolus
    • Round nucleus
    • Slightly basophilic cytoplasm
    • Cytoplasmic protrusion
  • Small cell variant
    • Small tumor cells with condensed chromatin
    • Small nucleolus visible by electron microscopy
  • Cerebriform (Sézary cell-like) variant
    • Irregular nuclear outline
    • Similar to cerebriform nucleus of Sézary cells seen in mycosis fungoides

Electrocardiogram

There are no ECG findings associated with T-cell prolymphocytic leukemia.

X-ray

There are no x-ray findings associated with T-cell prolymphocytic leukemia. However, an x-ray may be helpful in the diagnosis of complications of T-cell prolymphocytic leukemia, which include pleural effusion and lung involvement.

Echocardiography or Ultrasound

There are no echocardiography findings associated with T-cell prolymphocytic leukemia.

Ultrasound may be helpful in the diagnosis of T-cell prolymphocytic leukemia. Findings on an ultrasound suggestive of/diagnostic of T-cell prolymphocytic leukemia include hepatomegaly and splenomegaly.

CT scan

CT scan may be helpful in the diagnosis of T-cell prolymphocytic leukemia. Findings on an CT scan suggestive of/diagnostic of T-cell prolymphocytic leukemia include hepatomegaly and splenomegaly.

MRI

There are no MRI findings associated with T-cell prolymphocytic leukemia.

Other Imaging Findings

There are no specific imaging findings associated with T-cell prolymphocytic leukemia.

Other Diagnostic Studies

Flow cytometry and immunohistopathology must be done to diagnose T-cell prolymphocytic leukemia.

Treatment

Medical Therapy

• The mainstay of therapy for T-cell prolymphocytic leukemia, include:

• Alemtuzumab (anti-CD52)

• T-cell prolymphocytic leukemia is often resistant to therapy.

Surgery

• Autologous and allogeneic stem cell transplants is the mainstay of therapy for patients who achieve remission.

Primary Prevention

• There are no established measures for the primary prevention of T-cell prolymphocytic leukemia.

Secondary Prevention

• There are no established measures for the secondary prevention of T-cell prolymphocytic leukemia.