Table 1.

Mature T-cell lymphoproliferative disorders with a leukemic presentation.

	T-PLL [6,7,11,18,19]	T-LGL [20,21,22]	ATLL [16,23,24]	NK-Cell LGL [21]	Sézary Syndrome [25,26,27]	Aggressive NK-Cell Leukemia [17,28]
Epidemiology	The incidence in Western countries is 2 per 1,000,000 people per year. T-PLL accounts for about 2% of mature leukemias.	Accounts for 2% to 5% of chronic lymphoproliferative disorders. The overall incidence is 0.72 per 1,000,000 people per year.	More common in parts of the world that are endemic for HTLV-1, including Japan, the Caribbean, and Central and South America. The global estimation of new cases is approximately 3000 per year.	Accounts for less than 5% of LGL disorders, is predominantly observed in Asia, and tends to affect individuals of younger age.	The annual incidence rate of SS is 1 per 10 million per year. SS represents 3% of all cutaneous lymphomas.	A very rare disease, predominantly in Asia. Median age 37 years (range 10–78). More frequent in males than females (male-to-female ratio: 1.3:1).
White Blood Cell Count (WBC)	Most patients present with extreme lymphoctosis (≥100,000/µL).	1.6–49.1 × 109/L (median count 5.5 × 109/L)	Acute type: 3.9–296 × 109/L (median count 88 × 109/L). Chronic type: 10.4–17 × 109/L (median count 17 × 109/L). Lymphomatous type: 1.1–45.3 × 109/L (median count 7.5 × 109/L).	Similar WBCs as in T-LGL. Blood LGL count of >700/μL.	The median white blood cell count is 21 × 109/L. The Sézary cell count is ≥1000 cells/μL.	WBC count in aggressive NK-cell leukemia varies widely and can be high, with a median count of 2.80 × 109/L (range, 0.29–57 × 109/L).
Histology	Three morphologic variants have been recognized (see Section 3).	Neoplastic cells cannot be differentiated cytologically from normal reactive cytotoxic lymphocytes.	In the acute type, neoplastic cells feature hyperchromatic nuclear chromatin and deeply lobulated nuclear contours: “flower cells”. In the chronic type, the neoplastic cells show subtle cytological atypia.	The histological features of NK-cell LGL are indistinguishable from those of T-LGL.	Atypical lymphocytes with cerebriform nuclei that are larger than normal lymphocytes and have hyperchromatic nuclei. These features are not specific, as similar morphological features can be observed in reactive lymphocytes in autoimmune disorders.	Neoplastic cells are medium to large, with moderate amounts of basophilic agranular cytoplasm, highly irregular nuclear contours, and a distinct open chromatin pattern with visible nucleoli.
Phenotype	Usually CD3+. CD4+ and CD8− is most common, however co-expression of CD4 and CD8 is also observed.	CD3+, CD16+, CD27−, CD28−, CD45R0−, CD45RA+, and CD57+. Ta/b > Tg/d. CD8+ > CD4+. CD94 is positive in 20% of CD8+ and in 2% of CD4+ cases.	Preserved expression of pan-T-cell markers (CD2, CD3, CD4, CD5) with strong expression of CD25 and FoxP3, and frequent loss of CD7.	Characterized by CD2+, sCD3−, CD3e+, TCRa/b−, CD4−, CD8+, CD16+, and CD56+. Expression of CD94 is detected in more than 95% of the cases. KIR expression is detected in 53% of cases.	Usually CD3+, CD4+ and CD8−. The aberrant loss of pan-T-cell antigens, including CD2, CD3, CD4, CD5, CD7, and/or CD26 is frequently seen.	Characterized by the expression of CD2, cytoplasmic CD3, CD7, CD16, and CD56, while the expression of surface CD3 is negative. Expression of CD94 is detected in more than 95% of cases.
Molecular features	TCL1A overexpression, combined with loss of ATM appears unique to T-PLL (see Section 5).	Activating mutations in genes such as STAT3-STAT5b, and NFKB are common.	Most cases exhibit intricate cytogenetic abnormalities that result from the detrimental impact of the viral-encoded TAX. Recurrent loss-of-function mutations in CIC/ATXN1 complex are detected in up to 50% of cases.	Mutations in STAT3 are observed in less than 10% of the cases, and STAT5b mutations are not detected.	Commonly altered genes in Sézary syndrome include ZEB1, STAT5B, FAS, ARID1A, CDKN2A, and TP53.	Activating mutations in JAK-STAT pathway genes, particularly STAT3 and STAT5B are detected. Mutations in tumor suppressor genes, such as TP53 are frequent.
Clinical features	Generally presents with extreme lymphocytosis, anemia and thrombocytopenia in the 6th to 7th decade of life.	At the time of diagnosis, approximately one-third of patients are asymptomatic. The initial presentation is typically associated with cytopenias (anemia or neutropenia).	Caused by HTLV-1 infection. The acute and chronic types usually present with leukemia, hepatosplenomegaly, and hypercalcemia. The lymphomatous type does not exhibit leukocytosis or hepatosplenomegaly.	Characterized by a chronic and indolent clinical course, that is similar to T-LGL. The 10-year survival rate is around 70%.	Characterized by erythroderma with severe pruritus and generalized lymphadenopathy.	Patients typically present with fever, hepatosplenomegaly, hemophagocytic lymphohistiocytosis and hyperferritinemia.