INTRODUCTION — The peripheral T cell lymphomas are a heterogeneous group of generally aggressive neoplasms that constitute less than 15 percent of all non-Hodgkin lymphomas in adults [1,2]. (See "Classification of hematopoietic neoplasms".)
Among these, in decreasing frequency of occurrence, are:
●Peripheral T cell lymphoma, not otherwise specified
●Anaplastic large cell lymphoma, primary systemic type
●Angioimmunoblastic T cell lymphoma
●Extranodal NK/T cell lymphoma, nasal type
●Subcutaneous panniculitis-like T cell lymphoma
●Enteropathy associated T cell lymphoma
●Hepatosplenic T cell lymphoma
Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) is a heterogeneous group of predominantly nodal T cell lymphomas derived from various types of mature T cells that do not meet the criteria for the other specifically defined subtypes of PTCL listed above. Although PTCL, NOS accounts for the largest number of patients with PTCL in Western countries, it is likely that this group of tumors represents a conglomerate of many not yet identified PTCL subtypes.
Although a variety of morphologic subtypes have been described, no consistent immunophenotypic, genetic, or clinical features have been associated with a large fraction of the PTCL. Therefore, for the time being, these presumably diverse cases are lumped under the heading PTCL, NOS, or "unspecified." Previously, they were classified as diffuse small cleaved, mixed, large cell and immunoblastic in the Working Formulation [3,4].
The clinical presentation, pathologic features, and diagnosis of PTCL, NOS will be discussed here. The other NK/T cell lymphomas and the pathobiology and treatment of the PTCLs are discussed separately. (See "Initial treatment of peripheral T cell lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma".)
EPIDEMIOLOGY — PTCL, NOS is the most common subtype of PTCL in Western countries, accounting for approximately 30 percent of PTCL and approximately 4 percent of non-Hodgkin lymphomas (NHLs) overall [1,3,5-7]. The incidence of PTCL, NOS increased in the United States from approximately 0.1 cases per 100,000 population in 1992 to approximately 0.4 cases per 100,000 population in 2006 [8]. This increase may reflect increased awareness and improved diagnostic methods. The incidence is higher in Asia where PTCLs account for 15 to 20 percent of all NHLs and approximately 20 to 25 percent of those cases are classified as PTCL, NOS [9].
In the United States, the incidence is highest in individuals of African descent, lower among White people (both Hispanic individuals and non-Hispanic individuals) and individuals of Asian/Pacific Island descent, and lowest among American Indian/Alaskan native people [10].
Most patients are adults with a median age at diagnosis of 60 years [9]. The diagnosis is more common in men than women by a ratio of approximately 2:1 [11].
CLINICAL FEATURES — Most patients with PTCL, NOS present with generalized lymphadenopathy with or without extranodal disease [9,11,12]. Approximately 38 percent of patients have nodal disease alone, 49 percent have nodal and extranodal disease, and 13 percent have extranodal disease without evidence of nodal involvement [11]. Hepatomegaly and splenomegaly are seen in 17 and 24 percent of patients, respectively. Approximately 14, 17, 26, and 43 percent of cases are stage I, II, III, and IV, respectively. The bone marrow is involved in 20 percent of cases and many others demonstrated infiltration of the liver and/or spleen. While circulating lymphoma cells may be seen, leukemic presentations are rare [1]. Some cases are associated with eosinophilia, pruritus, and/or hemophagocytosis (picture 1) [13]. Thrombocytopenia and anemia are seen in one-quarter of patients [11].
The skin and gastrointestinal tract are the most commonly involved extranodal sites [1,14-16]. Less commonly involved sites include the lung, salivary gland, and central nervous system. Systemic B symptoms (fever, night sweats, weight loss) are present in approximately 35 percent of patients [11]. Half of cases are associated with an elevated lactate dehydrogenase level and 14 percent have hypergammaglobulinemia.
PATHOLOGY — PTCL, NOS is a heterogeneous group of tumors comprised of malignant cells of T cell origin that exhibit widely varying histology.
Histology — Lymph nodes usually demonstrate effacement of the normal architecture by sheets of atypical lymphoid cells in a paracortical or diffuse pattern (picture 2) [1]. The tumor cells have no characteristic morphologic features and typically are comprised of variable mixtures of small, intermediate, and large atypical cells [17,18]. These cells contain pleomorphic, irregular, vesicular, or hyperchromatic nuclei with prominent nucleoli and usually exhibit a high mitotic rate [1]. They sometimes have clear cytoplasm, a morphologic feature suggestive of a T cell phenotype.
Typically, there are varying numbers of admixed eosinophils, plasma cells, resting or activated B cells, and epithelioid histiocytes (activated macrophages) [19]; the term lymphoepithelioid cell lymphoma (Lennert's lymphoma) has been used in the past for cases rich in epithelioid histiocytes (picture 3) [19], and is now considered a variant of PTCL, NOS.
Two additional variants include a form characterized by growth in a paracortical pattern, often surrounding reactive B cell follicles, the so-called "T-zone" variant, and another in which the malignant T cells grow in aggregates within follicles, the so-called "follicular" variant.
Biopsy of involved extranodal tissues demonstrates a diffuse infiltrate of similar atypical lymphoid cells. Skin involvement commonly takes the form of infiltrates in the dermis and subcutis and can result in nodules with central ulceration [20]. Splenic involvement can vary from solitary fleshy nodules to diffuse involvement of the white or red pulp [20].
Immunophenotype — There is no characteristic immunophenotype for PTCL, NOS. T cell-associated antigens are variably expressed (CD3+/-, CD2+/-, CD5+/-, CD7-/+). These tumors are generally negative for B cell associated antigens [18,21], but rare tumors may express CD20 [22], sometimes leading to diagnostic confusion.
In most cases, one or more "mature" T cell antigens are lost, such as CD5 or CD7. Expression of CD4 and CD8 is variable. The majority of tumors express CD4 only, but some tumors may be CD4-/CD8-, CD4-/CD8+, or CD4+/CD8+. Most cases express alpha/beta T cell receptors (TCR beta positive), while a minority expresses gamma/delta T cell receptors (TCR delta-positive).
Genetic features — Clonal T cell receptor (TCR) gene rearrangements are usually, but not always, detected; immunoglobulin (Ig) genes are germline [23,24]. Although approximately 90 percent of PTCLs demonstrate cytogenetic abnormalities, none is specific for PTCL, NOS [25-30]. Many patients demonstrate chromosomal gains in 7q, 8q, 17q, and 22q, and chromosomal losses in 4q, 5q, 6q, 9p, 10q, 12q, and 13q [1].
The most common chromosomal translocations are t(7;14), t(11;14), inv(14), and t(14;14) [31]. Analogous to B cell lymphomas where immunoglobulin (Ig) loci (BCR genes) are affected, these translocations involve TCR genes located at 14q11 (TCR alpha/delta), 7q34-35 (TCR beta), and 7p15 (TCR gamma). However, translocations involving the TCR genes in PTCLs are much less frequent than translocations involving the Ig genes in B cell lymphomas. This is likely due to the fact that mature B cells continue to diversify their Ig genes in germinal centers through somatic hypermutation and class switching, events that are prone to errors that can result in translocations, whereas the TCR genes of mature T cells are genomically stable and presumably much less likely to participate in oncogenic rearrangements.
Efforts are underway to use genomic profiling and other techniques to further divide this heterogeneous group of tumors [32-35]. Gene expression profiles (GEPs) of PTCL, NOS are clearly distinct from resting normal T cells and are most closely related to activated CD4+ or CD8+ peripheral T cells [36]. Two subgroups of PTCL, NOS, with distinct gene expression profiles driven by the transcription factors TBX-21 or GATA-3, which normally play a role in the differentiation of CD4+ T cells into TH1 and TH2 helper cells, respectively, have been also described [37-39]. In addition, PTCL, NOS, angioimmunoblastic T cell lymphoma, and anaplastic large cell lymphoma have distinctive gene expression profiles [36,39-41].
DIAGNOSIS — PTCL, NOS is a diagnosis made based upon the results of a tissue biopsy (usually lymph node biopsy) that demonstrates evidence of a T cell lymphoma that does not meet the criteria for other subtypes of T cell lymphoma including (table 1):
●Anaplastic large cell lymphoma
●Angioimmunoblastic T cell lymphoma
●Extranodal NK/T cell lymphoma, nasal type
●Subcutaneous panniculitis-like T cell lymphoma
●Enteropathy associated T cell lymphoma
●Hepatosplenic T cell lymphoma
As described above, histologic examination of the biopsy material usually demonstrates variable mixtures of small, intermediate, and large atypical cells. In many instances, the histologic features are sufficiently atypical (eg, complete nodal effacement by atypical lymphoid cells) that a diagnosis of lymphoma can be made with certainty, but evaluation of the immunophenotype by either immunohistochemistry or flow cytometry is essential to confirm the T cell origin of the tumor. Immunohistochemistry is more reliable, because large lymphoid cells are sometimes lost or disrupted during tissue processing required for performance of flow cytometry.
The immunophenotype of PTCL, NOS varies greatly from case to case, but always demonstrates expression of one or more of the pan-T antigens (ie, CD2, CD3, CD5, CD7). Roughly half of cases demonstrate an aberrant immunophenotype, defined by the loss of a pan-T cell antigen that is expressed by most normal mature T cells (eg, CD5 or CD7) [42,43]. Detection of surface CD3 (best assessed by flow cytometry) can also be helpful, since this finding excludes rare lymphomas of natural killer cell origin. In difficult or equivocal cases, molecular detection of a clonal T cell receptor (TCR) rearrangement, performed using a PCR-based assay, can be very helpful. While the majority of PTCL, NOS has cytogenetic abnormalities, none are specific. The genetics of PTLC, NOS are also heterogeneous [44,45], and it remains to be determined if DNA sequencing will prove useful in delineating new molecular subtypes.
Because PTCL, NOS is a heterogeneous category and essentially a diagnosis of exclusion, the diagnostic agreement rate among expert hematopathologists is only about 75 percent [11]. As with other T cell lymphomas, knowledge of pertinent clinical and laboratory findings improves diagnostic accuracy.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PTCL, NOS includes other T cell lymphomas and B cell lymphomas (including Hodgkin lymphoma) that have similar morphologic and/or immunophenotypic features, and benign disorders that result in hyperplasia of nodal paracortical T cell zones, such as hypersensitivity reactions and unusually prolonged or robust immune responses to viral infections (eg, with Epstein Barr virus) (table 1). Thin needle biopsies can be particularly difficult to interpret as architectural effacement cannot be assessed, and the malignant mixed cell infiltrate can mimic a reactive process. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Type of biopsy'.)
Angioimmunoblastic T cell lymphoma — Angioimmunoblastic T cell lymphoma (AITL) is another relatively common subtype of T cell lymphoma that presents with generalized lymphadenopathy and systemic symptoms. Like PTCL, NOS, involved lymph nodes demonstrate partial or complete effacement of the normal architecture by a predominantly paracortical infiltrate of atypical lymphoid cells of different sizes and inflammatory cells. There is prominent neovascularization with arborizing high endothelial venules and an expansion of follicular dendritic cells that often surround tumor cells with abundant clear cytoplasm. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)
The distinction between PTCL, NOS and AITL is based upon the absence of morphologic features typical of AITL and the immunophenotype of the tumor cells. Unlike AITL, the tumor cells in PTCL, NOS do not typically express CD10, BCL6, PD1, or CXCL13 [1,2], which are markers expressed by normal T follicular helper cells. AITL also appears to have a relatively unique pattern of driver mutations in genes such as DNMT3A, TET2, IDH2, and RHOG [44], but further work is needed to determine the role of DNA sequencing in subtyping PTCL.
Anaplastic large cell lymphoma — Anaplastic large cell lymphoma (ALCL) is a lymphoma of T cell or null cell type that typically presents with painless lymphadenopathy with or without systemic symptoms. On histology, the tumor is composed in part of large lymphoma cells with horseshoe-shaped nuclei and prominent nucleoli (hallmark cells). ALCL demonstrates homogeneous, strong expression of CD30 in a membrane and golgi pattern. T cell antigens are also commonly expressed.
A proportion of PTCL, NOS tumors express CD30 in a subset of cells, but not in the diffuse pattern typical of ALCL. ALCL is often positive for epithelial membrane antigen and ALK, the latter due to the presence of ALK gene rearrangements, all of which are absent from PTCL, NOS. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma".)
It is important to note that anaplastic large cell lymphoma that is ALK-negative is not always easily distinguished from CD30+ PTCL, NOS, and yet is considered a distinct entity in the 2016 revision of the WHO classification scheme [2]. Some cases of ALK-negative ALCL have been found to harbor chromosomal rearrangements of DUSP22 and TP63 [46]. Reports suggest that cases of ALCL with DUSP22 rearrangement appear to have a prognosis that mimics that of ALK-positive ALCL and is superior to that of those with TP63 abnormalities [46,47].
Hodgkin lymphoma — Both PTCL, NOS and classical Hodgkin lymphoma (HL) may contain cells resembling Reed-Sternberg cells in an inflammatory background. Uncommonly, PTCL, NOS can express CD30 and rarely are positive for CD15, markers that are typically positive in classical forms of HL. However, PTCL, NOS is differentiated from HL by the absence of PAX5, a B cell-specific factor seen in most cases of HL, and by the expression of alpha/beta T cell receptors (TCR beta positive) and other T cell markers. (See "Hodgkin lymphoma: Epidemiology and risk factors".)
Adult T cell leukemia-lymphoma — Adult T cell leukemia-lymphoma (ATL) is another T cell lymphoma that typically presents with generalized lymphadenopathy, hepatosplenomegaly, immunosuppression, hypercalcemia, lytic bone lesions, and/or skin lesions. The malignant cell of origin in ATL is a transformed HTLV-I infected mature helper (CD4+) T-lymphocyte. Nodal ATL cannot be reliably distinguished from PTCL, NOS on morphologic or immunophenotypic grounds [11] and can only be excluded with certainty if HTLV-I studies (generally serology) are negative, particularly in patients from regions where HTLV-1 is endemic. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)
T cell histiocyte rich large B cell lymphoma — T cell histiocyte rich large B cell lymphoma (THRLBCL) is a variant of diffuse large B cell lymphoma (DLBCL) that can resemble PTCL, NOS. In THRLBCL, the tumor cells are a minor fraction of the total cellularity, which consists mainly of reactive T cells and histiocytes. Distinction from PTCL, NOS is usually not difficult, as the malignant B cells in THRLBCL express pan B cell markers (eg, CD19, CD20, CD22, CD79a), and will usually show IgH gene rearrangements. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'T cell histiocyte-rich large B cell lymphoma'.)
Granulomatous lymphadenitis — Some cases of PTCL, NOS generate a granulomatous host response in involved tissues, and in some instances the granulomas are so numerous that they overshadow the neoplastic lymphoid cells in the background. The most important clue is careful morphologic inspection of lymphoid cells, which usually show a significant degree of cytologic atypia in PTCL, NOS. Difficult cases can be distinguished by immunophenotyping and polymerase chain reaction-based assays of T cell receptor rearrangements, which usually reveal a polyclonal pattern in granulomatous lymphadenitis. Care must be taken not to over-interpret a dominant clone within a reactive T cell expansion in small biopsy specimens.
Paracortical hyperplasia — Some cases of PTCL, NOS demonstrate a perifollicular (T-zone) growth pattern that is similar to that seen in benign paracortical hyperplasias, which in certain immune reactions may include a high fraction of large, rapidly-dividing T immunoblasts that simulate the appearance of lymphoma (eg, in responses to viral infections such as acute mononucleosis). Unlike PTCL, NOS, the T cells in benign hyperplasias have normal immunophenotypes and are typically polyclonal when tested by polymerase chain reaction-based assays, lacking the clonal T cell receptor rearrangements that are seen in PTCL, NOS. As in all reactive immune processes, care must be taken not to over-interpret a dominant clone within a reactive T cell expansion in small biopsy specimens.
TREATMENT — The treatment of PTCL, NOS is discussed separately. (See "Initial treatment of peripheral T cell lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma".)
PROGNOSIS — The clinical course of PTCL, NOS is aggressive, and relapses are common [5,11,48-51]. Both disease stage at diagnosis and the international prognostic index (IPI) score used for other non-Hodgkin lymphomas (NHLs) have correlated with overall survival in these patients (table 2) [52]. Patients with PTCL generally have a worse prognosis, stage for stage, than patients with B cell NHL [6,16,49,53]. However, some patients may attain long term survival with treatment that incorporates transplantation (see "Initial treatment of peripheral T cell lymphoma" and "Prognosis of diffuse large B cell lymphoma", section on 'International Prognostic Index').
Prior to the routine use of rituximab for B cell NHL, a retrospective analysis compared the ability of the IPI to predict outcomes in 288 patients with PTCL and 1595 patients with B cell NHL [53]. When compared with patients with B cell NHL, patients with PTCL demonstrated the following:
●A similar distribution of IPI scores. For all patients with PTCL, IPI scores of zero, 1, 2, and ≥3 were seen in 13, 17, 24, and 45 percent, respectively. However, the distribution varied by PTCL subtype. When compared with other subtypes of PTCL, patients with anaplastic large cell lymphoma (20 percent of the total) were more likely to have an IPI of zero (39 versus 7 percent) or 1 (24 versus 15 percent).
●Similar five-year overall survival rates for patients with IPI scores of zero (82 versus 81 percent) or 1 (73 versus 71 percent).
●Worse five-year overall survival rates for patients with IPI scores of 2 (58 versus 63 percent) or ≥3 (35 versus 52 percent).
Other prognostic scoring systems have been proposed, but require further validation. The most popular of these, the prognostic index for PTCL, unspecified (PIT) assigns one point for each of the following criteria (table 3) [54]:
●Age >60 years
●Increased serum lactate dehydrogenase
●Eastern Cooperative Oncology Group (ECOG) performance status ≥2
●Bone marrow involvement
A retrospective multicenter study of 385 patients with PTCL, NOS was used to develop this prognostic score and demonstrated an association between increased score and decreased survival [54]. Patients with zero, one, two, or three to four of these adverse prognostic factors had five-year overall survival rates of 63, 53, 33, and 18 percent, respectively. A second retrospective analysis of a smaller population also found the PIT score to correlate with progression-free and overall survival rates [55]. However, when applied to another cohort of 340 cases of PTCL, NOS, the PIT was not superior to the IPI for predicting survival [11].
Another system, the International peripheral T cell lymphoma Project score (IPTCLP), incorporates information on age (≤60 versus >60), ECOG performance score (≤1 versus >1), and platelet count (≤150K versus >150K) to divide patients into four groups [56]. When applied to 121 patients with PTCL, patients with zero, 1, 2, or 3 risk factors demonstrated five-year overall survival rates of 58, 15, 5, and zero percent, respectively.
Other models have suggested the following features as potential predictors of a poor response: Ki-67 positivity of ≥80 percent, Epstein-Barr virus positivity, the presence of systemic B symptoms, low albumin, mediastinal lymphadenopathy, the presence of a "proliferation signature", and the expression of GATA-3 or GATA-3 target genes [37,38,55,57-61].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)
SUMMARY — Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) is a heterogeneous group of predominantly nodal T cell lymphomas that do not meet the criteria for the other specifically defined subtypes of PTCL.
●PTCL, NOS is the most commonly diagnosed type of PTCL in Western countries accounting for approximately 30 percent of cases. The incidence varies geographically with the highest incidence found in Asia. (See 'Epidemiology' above.)
●Most patients present with generalized lymphadenopathy with or without extranodal disease. Systemic B symptoms are common and some cases demonstrate blood eosinophilia, pruritus, and/or hemophagocytosis. (See 'Clinical features' above.)
●The diagnosis of PTCL, NOS is a diagnosis of exclusion made based upon the results of a tissue biopsy (usually lymph node biopsy) that demonstrates evidence of a T cell lymphoma that does not meet the criteria for other subtypes of T cell lymphoma (table 1). Evaluation of the immunophenotype by either immunohistochemistry or flow cytometry is essential to confirm the T cell origin of the tumor. (See 'Diagnosis' above.)
●Histology usually demonstrates a non-specific mixture of small, intermediate, and large atypical cells (picture 2). (See 'Histology' above.)
●The immunophenotype of PTCL, NOS, varies greatly from case to case, but always demonstrates expression of one or more of the pan-T antigens (ie, CD2, CD3, CD5, CD7). Roughly half of cases demonstrate an aberrant immunophenotype, defined by the loss of a pan-T cell antigen that is expressed by all normal mature T cells (eg, CD5 or CD7). (See 'Immunophenotype' above.)
●The differential diagnosis of PTCL, NOS includes other T cell lymphomas and B cell lymphomas (including Hodgkin lymphoma) that have a similar morphology and/or immunophenotype. (See 'Differential diagnosis' above.)
●The clinical course of PTCL, NOS is aggressive, and if remission is achieved, relapses are common. Both disease stage at diagnosis and the international prognostic index (IPI) score used for other NHLs have correlated with overall survival in these patients (table 2). Patients with PTCL generally have a worse prognosis, stage for stage, than patients with B cell non-Hodgkin lymphoma. (See 'Prognosis' above.)
