PTCL-NOS are represented by nodal or extranodal T-cell lymphomas not otherwise categorized as any specific entity in the current WHO classification. These tumors represent 60–70% of all PTCLs, and 5–7% of all NHLs. They occur more commonly in adults with a median age of 60 years and have a slight male predominance.4–6 Although lymph node involvement predominates in the majority of cases, these lymphomas often disseminate to the bone marrow, liver, spleen, and other extranodal sites such as the skin and lung. They rarely have a leukemic presentation.5,6 Patients often present with unfavorable clinical characteristics including B symptoms, elevated lactate dehydrogenase (LDH) levels, high tumor burden, advanced disease (Stage III or IV), and poor performance status.5,6

The AITL subtype is characterized by a specific clinical syndrome and polymorphic infiltrate involving lymph nodes, with proliferation of high endothelial venules in a tree-like pattern and irregular proliferation of follicular dendritic cells (FDC) with predominantly perivascular distribution. AITL represents the second most common subtype of PTCL (15–20% of cases) with its prevalence only being exceeded by PTCL-NOS. It occurs most commonly in elderly patients (aged 60–65 years), with a slight male predominance.7

Typical cases of AITL show acute or subacute systemic features that may mimic drug reactions or systemic infections. Clinically, AITL presents as small and generalized lymphadenopathy, hepatosplenomegaly, and constitutional symptoms. Maculopapular rash occurs in 50% of cases and paraneoplastic manifestations such as arthritis, vasculitis, serous effusions, and neurological manifestations are not uncommon. Laboratory features include eosinophilia, polyclonal hypergammaglobulinemia, elevated serum LDH and erythrocyte sedimentation rate (ESR), as well as circulating autoantibodies (cryoagglutinins, cryoglobulins, immune complexes, positive direct Coombs test) and paraneoplastic phenomena of an immune nature (hemolytic anemia, leukocytoclastic vasculitis, rheumatoid arthritis, and autoimmune thyroid disease).1,4,7

ALCL is a PTCL characterized by large polymorphic lymphoid CD30+ cells with abundant cytoplasm and horseshoe- or kidney-shaped nuclei. The three recognized subtypes are ALCL-ALK+, ALCL-ALK−, and primary cutaneous anaplastic lymphoma.8 ALCL-ALK+ predominates in younger patients, with a median age of 30 years, and represents 3–5% of NHLs in adults and 30% of NHLs in children, with a male predominance. Extranodal involvement is frequent, and 50% of cases are diagnosed at an advanced stage (III or IV) and in patients with B symptoms. The most commonly involved sites include the skin, subcutaneous tissue, bone, lung, and liver. Bone marrow involvement occurs in 10–30% of cases, but the leukemic phase is unusual and occurs more frequently in the small-cell morphological variant. It rarely presents with gastrointestinal and central nervous system involvement. Despite the advanced stage involving multiple extranodal sites, most patients present with low-risk or low-intermediate risk disease according to the International Prognostic Index (IPI), since performance status is frequently preserved and most patients are younger, with normal LDH levels at diagnosis.4,9

ALCL-ALK− is morphologically indistinct from ALCL-ALK+, but does not show chromosomal translocations involving the ALK gene or expression of the ALK protein. The disease predominates in the elderly; extranodal involvement occurs in up to half of cases and is usually diagnosed in patients with advanced stage disease who have B symptoms and aggressive disease. Recently, an unusual variant associated with prosthetic breast implants that has an indolent behavior has been described.8–10

An excisional tumor biopsy is essential for correct diagnosis. Needle biopsy guided by imaging is not recommended.1 It should be highlighted that for the correct diagnosis and classification of PTCL, histopathological analysis by an experienced hematopathologist using a large sample with a considerable amount of tissue that allows visualization of the broad pattern of lymph node infiltration is necessary, as well as applying a wide immunohistochemical panel.

In PTCL-NOS, the compromised lymph node shows paracortical or diffuse infiltration with loss of the normal lymph node architectural pattern. Although large tumor cells predominate, a few cases exhibit small neoplastic cells. The morphologic spectrum varies from monotonous to pleomorphic cells with an excess of mitotic cells (Figure 1). The WHO classification recognizes histological variants such as lymphoepitheliod lymphoma (Lennert lymphoma), follicular, and T-like zone. Phenotypically, it exhibits aberrant antigen expression characterized by a lack of T-cell markers such as CD5 and CD7. Most cases express the CD4 antigen, although some others may be CD8+, particularly the lymphoepitheliod variant. About 30% of PTCL-NOS express the CD30 marker, but the phenotypic profile and morphologic aspect allow it to be distinguished from ALCL-ALK− since the latter expresses epithelial membrane antigens (EMA) and contains cytotoxic granules. Distinguishing it from classical Hodgkin's lymphoma (HL) can be achieved by observing the expression of CD15, PAX-5, and Epstein–Barr virus (EBV). Also, PTCL-NOS present with a high proliferative rate, with Ki67 higher than 70%, and strong and homogeneous expression of CD3.1,4,11 Cases of PTCL CD30+/ALK− with no histologic similarity to classic ALCL should be categorized as PTCL-NOS.1 A monoclonal rearrangement of the T-cell receptor (TCR) gene is usually seen in PTCL-NOS by polymerase chain reaction (PCR); a cytogenetic abnormality with complex karyotype is the rule. In the subtype with a follicular growth pattern, it is common to observe the recurrent aberration t(5;9)(q33;q22) that produces the oncogenic protein ITK-SYK.11

Figure 1.

Morphologic aspects of Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). (A) Diffuse proliferation of atypical medium sized lymphoid cells. Note some intermingled eosinophils [hematoxylin and eosin (H&E)-stained section]. (B) Diffuse expression of CD3 by the neoplastic lymphoid cells. (C) These cells also express CD4. (D) CD7 antigen is only partially expressed by neoplastic T cells.

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The morphological aspects of classical AITL include a diffuse pattern of infiltration by polymorphic cells and variable proportions of atypical neoplastic T-cells together with small lymphocytes, histiocytes, immunoblasts, eosinophils, and plasma cells with peri-lymph node infiltration into subcortical sinuses. Likewise, there is prominent vascular proliferation with a tree-like pattern of endothelial venules and irregular proliferation of FDC. B immunoblasts are usually present in the paracortical region and may mimic HL (Figure 2). Neoplastic cells express a pattern of follicular T helper cells such as CD3+, CD4+, CD10+, BCL-6+, CXCL13+, PD1+, and ICOS+ cells. Indeed, vascular expansion can be demonstrated by immunohistochemistry for CD31 and CD34. Irregular proliferation of FDC can be defined by CD21, CD23, and CD35 staining that are often found with vessels. The B-cell-associated antigen markers, such as CD20 and CD79a, may show immunoblasts in the interfollicular areas. These cells are infected by EBV and are Reed-Sternberg-like cells mimicking classical HL.7,11–14 Most of the AITL cases contain a monoclonal population of T cells. The presence of B lymphocyte clones can be detected in up to 30% of cases and the EBV genome is detected in nearly 100%. Karyotypic aberrations occur in 70–80% of cases, mainly trisomy of chromosome 3 and 5, and an additional X chromosome.11,15

Figure 2.

Morphologic aspects of angioimmunoblastic T-cell lymphoma. (A) Proliferation of small to medium sized lymphoid cells with mild atypia surrounding prominent high endothelial venules. Occasional large cells are observed, as well as some plasmocytes (H&E-stained section). (B) The majority of neoplastic lymphoid cells express membrane CD3. (C) Neoplastic lymphoid cells also express CD10. (D) CD20 antibody highlights the large B immunoblasts. (E) Follicular dendritic cell meshwork expansion surrounding high endothelial venules is evident with CD21 immunostain.

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Although ALCL-ALK+ presents with a broad morphological spectrum, all cases contain a variable proportion of cells with eccentric nuclei (kidney-like or horseshoe-shaped) with an eosinophilic perinuclear area corresponding to the Golgi, and abundant cytoplasm; these cells are called ‘hallmark cells’. The morphological findings of this disease vary from small to very large malignant cells (Figure 3). In addition, five distinct morphological patterns are recognized including classical, lymphohistiocytic, small-cell, ‘Hodgkin-like’ variant, and mixed pattern.9,11 The classical variants represent 60–70% of all cases and their malignant cells are almost exclusively large and sometimes Reed-Sternberg-like. When the lymph node architecture is partially compromised, the cells grow within sinusoids and may simulate metastatic tumors. The cell phenotype exhibits diffuse positivity for CD30 and sometimes presents as a ‘perinuclear dot’ that corresponds to Golgi. Expression of the CD2 antigen is common, but CD45RO, CD5, and CD7 are usually negative. Most patients present with a CD4+/CD8− phenotype and show co-expression of cytotoxic antigens such as granzyme B, TIA-1, perforin and the EMA antigen.4,9,11 Most cases of ALCL-ALK+ have t(2;5)(p23;q35), resulting in the hybrid product NPM1-ALK. In these cases, the ALK protein can be found in both the cytoplasm and nucleus. About 90% of these lymphomas have a clonal rearrangement of the TCR gene. In addition to the classic t(2;5), a variant chromosome translocation involving the ALK gene and other genes located on chromosomes 1, 2, 3, 17, 19, 22, and X may occur. The morphological and phenotypic aspects of ALCL-ALK− cases are identical to those observed in ALCL-ALK+ cases.4,11,16

Figure 3.

Morphologic aspects of anaplastic large cell lymphoma-anaplastic lymphoma kinase (ALK) positive. (A) Diffuse proliferation of large, highly atypical cells, with prominent pleomorphism (H&E-stained section). Some hallmark cells can be observed; they present large multilobulated ‘horseshoe-like’ nuclei. Neoplastic cells show diffuse expression of (B) CD30; (C) CD43; (D) epithelial membrane antigens and (E) ALK-1. In this case, ALK-1 positivity present exclusive cytoplasmic pattern.

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Different studies have shown that the phenotype of T-cell lymphomas can be effectively stratified using the IPI.17,18 However, a Prognostic Index for T-cell Lymphomas (PIT) was developed in an attempt to produce more accurate prognostic indicators. This prognostic index identified four risk factors; age, serum LDH, performance status, and histopathological involvement of the bone marrow. Patients were stratified into four risk groups with 0, 1, 2, or more than 2 risk factors with overall survival (OS) of 62%; 53%, 33%, and 18% for each risk group, respectively.19

Another index is the modified Prognostic Index for T-cell Lymphoma (mPIT), which incorporates a biological variable (Ki67 expression) and clinical aspects such as age, LDH, and performance status. The mPIT distinguishes three different risk groups: good risk prognosis, intermediate risk, and poor risk.20 The International Peripheral T-cell Lymphoma Project (IPTCLP) proposed another prognostic score that includes age, performance status, and platelet count.18,21