Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified

INTRODUCTION — Peripheral T cell lymphomas (PTCLs) comprise a heterogeneous group of generally aggressive neoplasms of T cell origin that manifest as lymphadenopathy or extranodal involvement. Although PTCL includes multiple subtypes that are distinguished by clinical, pathologic, or genetic features, together they account for <15 percent of all non-Hodgkin lymphomas (NHL) in adults.

PTCL nosology is evolving as the underlying pathobiology and genetic features are better defined. PTCLs should be diagnosed and classified according to World Health Organization (WHO) 5^th edition [1] or the International Consensus Classification of Mature Lymphoid Neoplasms (ICC) [2], rather than earlier nosologic systems.

PTCL, not otherwise specified (NOS), is a heterogeneous group of predominantly nodal T cell lymphomas for which no consistent immunophenotypic, genetic, or clinical features have been defined. This category likely represents a conglomerate of multiple, as-yet-undefined PTCL subtypes. They were previously classified as "diffuse small cleaved, mixed, large cell and immunoblastic T cell lymphomas" in the Working Formulation [3,4].

At present, PTCL, NOS is a diagnosis of exclusion for mature T cell NHLs that do not meet criteria for other defined subtypes of PTCL. Among PTCLs, the most common subtypes in decreasing frequency of diagnosis are:

●PTCL, NOS

●Anaplastic large cell lymphoma, primary systemic type

●T follicular helper (Tfh) cell lymphoma, which includes angioimmunoblastic T cell lymphoma and related neoplasms

●Extranodal NK/T cell lymphoma, nasal type

●Subcutaneous panniculitis-like T cell lymphoma

●Enteropathy associated T cell lymphoma

●Monomorphic epitheliotropic intestinal T-cell lymphoma

●Hepatosplenic T cell lymphoma

The clinical presentation, pathologic features, and diagnosis of PTCL, NOS are discussed here. Management of PTCLs is discussed separately. (See "Initial treatment of peripheral T cell lymphoma".)

EPIDEMIOLOGY — Peripheral T cell lymphomas (PTCL), not otherwise specified (NOS), is the most common subtype of PTCL in Western countries, accounting for approximately 30 percent of PTCLs and 4 percent of non-Hodgkin lymphomas (NHLs) overall [3,5-8]. The incidence of PTCL, NOS increased in the United States from approximately 0.1 cases per 100,000 population in 1992 to 0.4 cases per 100,000 population in 2006 [9]. 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; approximately 20 to 25 percent of those cases are classified as PTCL, NOS [10].

Most patients are adults; median age at diagnosis is 60 years [10]. The diagnosis is more common in men than women by a ratio of approximately 2:1 [11]. In the US, the incidence is highest in individuals of African descent, it is lower among White people (both Hispanic individuals and non-Hispanic individuals) and individuals of Asian/Pacific Island descent, and it is lowest among American Indian/Alaskan native people [12].

CLINICAL FEATURES — Most patients with PTCL, NOS present with generalized lymphadenopathy, with or without extranodal disease [10,11,13].

●Clinical presentation - An international database of 340 cases of PTCL, NOS reported that 38 percent of patients had nodal disease alone, 49 percent had nodal plus extranodal disease, and 13 percent had extranodal disease without nodal involvement [11]. Hepatomegaly and splenomegaly were seen in 17 and 24 percent of patients, respectively, and bone marrow was involved in 20 percent of cases. Systemic B symptoms (fever, night sweats, weight loss) were reported in one-third of patients.

In that study, disease stage I, II, III, and IV accounted for 14, 17, 26, and 43 percent of cases, respectively [11].

●Extranodal involvement - Skin and gastrointestinal tract are the most common sites of extranodal disease [5,14-16]. Less frequently, lung, salivary gland, and central nervous system are involved. Half of cases display elevated serum lactate dehydrogenase (LDH) and 14 percent had hypergammaglobulinemia.

While circulating lymphoma cells may be seen, leukemic presentations are rare [5]. Some cases are associated with eosinophilia, pruritus, and/or hemophagocytosis (picture 1) [17]. Thrombocytopenia and anemia are seen in one-quarter of patients [11].

PATHOLOGY — PTCL, NOS is a heterogeneous group of tumors of T cell origin that exhibit 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) [5].

●Cytomorphology - Tumor cells of PTCL, NOS have no characteristic morphologic features and typically include variable mixtures of small, intermediate, and large atypical cells [18,19]. The cells contain pleomorphic, irregular, vesicular, or hyperchromatic nuclei with prominent nucleoli and usually exhibit a high mitotic rate [5]. They sometimes have clear cytoplasm, a morphologic feature suggestive of a T cell phenotype.

●Patterns of involvement - The malignant cells of PTCL are typically admixed with variable numbers of eosinophils, plasma cells, resting or activated B cells, and epithelioid histiocytes (activated macrophages).

Involved extranodal tissues demonstrate a diffuse infiltrate of 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].

Lymphoepithelioid cell lymphoma (Lennert's lymphoma) was previously applied as a label to cases rich in epithelioid histiocytes (picture 3) [21], which are now considered a variant of PTCL, NOS. The so-called "T-zone" variant is characterized by growth in a paracortical pattern, often surrounding reactive B cell follicles.

PTCLs with malignant T cells growing as aggregates within lymphoid follicles were previously classified as a "follicular" variant of PTCL, NOS. However, most T cell lymphomas with follicular growth patterns express markers of Tfh cells and are now classified as variants of T follicular helper (Tfh) cell lymphoma in the World Health Organization (WHO) Classification of Hematolymphoid Tumors, 5^th Edition (WHO5) [1] and the International Consensus Classification (ICC) of Lymphoid Neoplasms [2].

Immunophenotype — There is no characteristic immunophenotype for PTCL, NOS. T cell antigens are expressed variably and tumors are generally negative for B cell antigens. Some tumors may express both T cell and B cell antigens, which can lead to diagnostic challenges.

●T cell antigens - PTCL, NOS is usually characterized by an aberrant T cell phenotype.

In most cases, one or more mature T cell antigens are lost, while expression of CD4 and CD8 varies [22]. CD3, CD2, CD5, and CD7 are expressed variably, but CD5 and CD7 are frequently downregulated. A CD4-positive/CD8-negative immunophenotype is most common in nodal cases. Most cases express alpha/beta T cell receptors, which facilitates the distinction from gamma-delta T cell lymphomas and NK cell lymphomas.

●Other antigens - These tumors are generally negative for B cell antigens, but rare tumors may express CD20 [19,23,24]

CD15 may be positive and, rarely, may be co-expressed with CD30 [25], leading to possible confusion with classic Hodgkin lymphoma. CD15 expression is associated with an adverse prognosis [22].

Genetic features — Nearly all cases demonstrate cytogenetic abnormalities, but none is specific for PTCL, NOS. Clonal T cell receptor (TCR) gene rearrangements are usually detected, while immunoglobulin genes are germline.

●Chromosomal abnormalities - Although 90 percent of PTCLs demonstrate cytogenetic abnormalities, none is specific for PTCL, NOS [26-31]. The most common chromosomal translocations in PTCL, NOS are t(7;14), t(11;14), inv(14), and t(14;14) [32]. Many tumors demonstrate chromosomal gains in 7q, 8q, 17q, and 22q, and chromosomal losses in 4q, 5q, 6q, 9p, 10q, 12q, and 13q [5].

●Molecular events – Clonal T cell receptor (TCR) gene rearrangements are usually (but not always) detected, while immunoglobulin genes are germline [33,34]. Structural abnormalities involving tumor suppressor genes are much more frequent than aberrations of oncogenes, which are rare [35-38]. Efforts are underway to apply genomic profiling and other techniques to further classify this heterogeneous group of tumors [35-38].

•TCR-related rearrangements - The following gene loci are most often involved in chromosomal translocations in PTCL, NOS:

-14q11 (TCR alpha/delta [TRA/TRD])

-7q34-35 (TCR beta [TRB])

-7p15 (TCR gamma [TRG])

Less often, TRD (TCR delta) can be rearranged with IRF4 on chromosome 6p25, leading to overexpression of IRF4 (also known as MUM1) [39].

Analogous to B cell lymphomas where immunoglobulin (Ig) loci are affected, chromosomal translocations in PTCL typically involve TCR genes. However, translocations involving TCR genes in PTCLs are much less frequent than translocations involving the Ig genes in B cell lymphomas. This is likely because, while mature B cells continue to diversify their Ig genes in germinal centers through somatic hypermutation and class switching (events that are prone to errors and can result in translocations), TCR genes of mature T cells are genomically stable and presumably less likely to participate in oncogenic rearrangements.

•Tumor suppressors - The tumor suppressor genes CDKN2A, PTEN, and TP53 are most often affected. A study that included 63 cases of PTCL, NOS, reported CDKN2A deletion in 46 percent, PTEN deletion in 26 percent, and co-deletion of CDKN2A and PTEN (an aberration that appears to be highly specific for PTCL, NOS) in 13 percent of cases [40]. Structural abnormalities involving TP63 are also found [38].

Gene expression profiles (GEPs) of PTCL, NOS are clearly distinct from resting normal T cells and are most closely related to activated CD4-positive or CD8-positive peripheral T cells [41]. Two subgroups of PTCL, NOS, with distinct gene expression profiles have been described. These two profiles are driven by the TBX-21 or GATA-3 transcription factors, which normally play a role in the differentiation of CD4-positive T cells into Th1 and Th2 helper cells, respectively [42-44]. Other distinctive GEPs have been described with PTCL, NOS, angioimmunoblastic T cell lymphoma, and anaplastic large cell lymphoma [41,44-46].

DIAGNOSIS — PTCL, NOS and other lymphomas may be suspected in individuals with lymphadenopathy, splenomegaly, constitutional symptoms, and findings related to organ infiltration.

Biopsy specimen — Diagnosis of PTCL, NOS requires an adequate biopsy specimen. An excisional lymph node biopsy or a substantial incisional specimen of a node or other tissue biopsy should be obtained whenever possible. Thin needle biopsies are difficult to interpret, as architectural effacement cannot be assessed, and the typical mixed cell infiltrate can mimic a reactive process. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Type of biopsy'.)

Diagnostic criteria — PTCL, NOS is a diagnosis of exclusion. This heterogeneous category comprises predominantly nodal T cell lymphomas for which no consistent immunophenotypic, genetic, or clinical features have been defined. PTCL nosology is evolving as their pathobiology and molecular features are better defined. PTCLs should be diagnosed and classified according to World Health Organization (WHO) 5^th edition [1] or the International Consensus Classification of Mature Lymphoid Neoplasms (ICC) [2], rather than earlier nosologic systems.

Diagnosis of PTCL, NOS requires morphologic and immunophenotypic evidence for a T cell lymphoma that does not meet criteria for other PTCL subtypes (table 1). Diagnosis does not require documentation of genetic features, except to exclude other conditions. While most cases have cytogenetic abnormalities, the findings are heterogeneous, and no finding is specific for these disorders [47,48]. Assignment to a genetic subgroup of PTCL, NOS is not routinely incorporated into clinical diagnosis.

Because PTCL, NOS is a diagnosis of exclusion and it is a heterogeneous category of diseases, diagnostic agreement rate among expert hematopathologists is only 75 percent [11]. As with other T cell lymphomas, knowledge of pertinent clinical and laboratory findings improves diagnostic accuracy.

Morphology — Histologic examination of the biopsy material usually demonstrates variable mixtures of atypical small, intermediate, and large lymphoid cells. The tumor cells usually contain pleomorphic, irregular, vesicular, or hyperchromatic nuclei with prominent nucleoli and a high mitotic rate. In some cases, the neoplastic cells have clear cytoplasm, a morphologic feature that is suggestive of a T cell phenotype. (See 'Histology' above.)

The malignant cells of PTCL are typically admixed with varying numbers of eosinophils, plasma cells, resting or activated B cells, and epithelioid histiocytes (activated macrophages).

Immunophenotypic criteria — The immunophenotype of PTCL, NOS varies widely, but it must confirm the T cell origin of the tumor. Immunohistochemistry is more reliable than flow cytometry for establishing the immunophenotype, because large lymphoid cells are sometimes lost or disrupted during tissue processing for flow cytometry.

PTCL, NOS always demonstrates expression of at least one pan-T antigen (ie, CD2, CD3, CD5, CD7). Approximately half of cases have an aberrant immunophenotype, defined by the loss of a pan-T cell antigen (most often CD5 or CD7) that is expressed by most normal mature T cells [49,50]. Detection of surface CD3 (best assessed by flow cytometry) can also be helpful to exclude rare lymphomas of natural killer (NK) cell origin.

In difficult or equivocal cases, detection of a clonal T cell receptor (TCR) rearrangement, using a polymerase chain reaction (PCR)-based assay, can help to confirm a T cell origin of the tumor.

Exclude other categories of PTCL — Other subtypes of PTCL must be excluded to diagnose PTCL, NOS, including:

●Anaplastic large cell lymphoma

●T follicular helper (Tfh) cell lymphoma, which includes angioimmunoblastic T cell lymphoma and related neoplasms

●Extranodal NK/T cell lymphoma, nasal type

●Subcutaneous panniculitis-like T cell lymphoma

●Enteropathy associated T cell lymphoma

●Monomorphic epitheliotropic intestinal T-cell lymphoma

●Hepatosplenic T cell lymphoma

Two biological variants of PTCL, NOS have been described [51] but neither is currently considered a distinct subtype, according to WHO5 or ICC [1,2]. Gene expression profiling has described PTCL-TBX21 and PTCL-GATA3 according to the transcriptional programs of T-helper-1 (Th1) and T-helper-2 (Th2) cells, respectively [43]. These subgroups may be recognized using an immunohistochemistry-based algorithm of four markers (TBX21, CXCR3, GATA3, CCR4) [43,51,52]. The PTCL-GATA3 subgroup has been associated with a worse outcome in some studies and has greater genomic complexity [44]. The PTCL-TBX21 subgroup is more heterogeneous, has fewer copy number alterations, and more often has mutations in genes regulating DNA methylation; these cases are generally associated with better prognosis, but cases that express cytotoxic molecules in patients with impaired immunity are aggressive PTCL and mostly cluster with the PTCL-TBX21 subgroup [44,53].

Diagnosis and classification of various T cell lymphomas is discussed separately. (See "Classification of hematopoietic neoplasms", section on 'Mature T cell or NK cell lineage'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PTCL, NOS includes lymphomas with similar morphologic and/or immunophenotypic features, including T cell lymphomas (table 1), B cell lymphomas, and Hodgkin lymphoma. Certain benign disorders that cause hyperplasia of nodal paracortical T cell zones may also be included in the differential diagnosis.

Lymphomas — PTCL, NOS must be distinguished from other lymphomas and excluding other subtypes of PTCL is required to diagnose PTCL, NOS, as described above. (See 'Diagnosis' above.)

T follicular helper (Tfh) cell lymphoma, including angioimmunoblastic T cell lymphoma and related neoplasms — These relatively common subtypes of T cell lymphoma typically present with generalized lymphadenopathy and systemic symptoms. Involved lymph nodes demonstrate partial or complete effacement of the normal nodal architecture by a predominantly paracortical infiltrate of atypical lymphoid cells of different sizes, along with inflammatory cells. Expansion of follicular dendritic cell meshworks is characteristic, and some cases have a follicular growth pattern. 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. Many cases also show an expansion of Epstein-Barr virus (EBV)-positive B cells in the background.

PTCL, NOS is distinguished from Tfh lymphomas by the absence of the characteristic morphologic features and tumor cell immunophenotype of Tfh lymphomas. PTCL, NOS does not usually express CD10, BCL6, PD1, or CXCL13, which are markers expressed by normal T follicular helper cells [5,54]. Tfh cell lymphomas also have a distinctive pattern of mutations in genes such as DNMT3A, TET2, IDH2, and RHOG [47]. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)

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. Histologically, the tumor includes large lymphoma cells with horseshoe-shaped or embryoid nuclei (hallmark cells) and prominent nucleoli. ALCL demonstrates homogeneous, strong expression of CD30 in a membrane- and golgi-associated pattern. T cell antigens are also commonly expressed.

Some PTCL, NOS tumors express CD30 in a subset of cells, but not in the diffuse pattern typical of ALCL. Furthermore, ALCL is often positive for epithelial membrane antigen and ALK, the latter due to the presence of ALK gene rearrangements, both of which are absent from PTCL, NOS. Although ALK-negative ALCL is considered a distinct entity, it is not always easily distinguished from CD30-positive PTCL, NOS [1,2]. However, some cases of ALK-negative ALCL can be identified by chromosomal abnormalities that rearrange DUSP22 or TP63 [55]. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

Hodgkin lymphoma — Both PTCL, NOS and classic Hodgkin lymphoma (cHL) may contain cells that resemble Reed-Sternberg cells in an inflammatory background. Both CD30 and CD15 are typically positive in cHL; PTCL, NOS can express CD30, but these tumors rarely express CD15. PTCL, NOS is differentiated from cHL by the absence of PAX5 (a B cell-specific factor seen in most cases of cHL) and by expression of alpha/beta T cell receptors and other T cell markers. (See "Hodgkin lymphoma: Epidemiology and risk factors".)

Adult T cell leukemia-lymphoma — Adult T cell leukemia-lymphoma (ATL) 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-positive) T-lymphocyte. Nodal ATL cannot be reliably distinguished from PTCL, NOS on morphologic or immunophenotypic grounds, but it can be excluded with certainty if HTLV-I studies (generally serology) are negative, particularly in patients from regions where HTLV-1 is endemic [11]. (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 large B cell lymphoma 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 usually show rearrangements of Ig heavy chains. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'T cell histiocyte-rich large B cell lymphoma'.)

Non-malignant disorders — Non-malignant disorders that can resemble PTCL, NOS include hypersensitivity reactions and prolonged or robust immune responses to Epstein-Barr virus or other viruses. For 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.

Autoimmune lymphoproliferative syndrome (ALPS) — ALPS is an inherited disorder usually caused by germline loss-of-function mutations in FAS (CD95), FASLG (FAS ligand), or CASP10 (caspase 10), which participate in a signaling pathway that leads to lymphocyte apoptosis. Characteristically, ALPS presents in childhood with lymphadenopathy, organomegaly, and autoimmune cytopenias. Lymph nodes show paracortical expansion by T cells expressing T cell alpha-beta receptors and CD3 and are negative for CD4 and CD8; this is often accompanied by follicular hyperplasia. Variable numbers of the T cells have an immunoblastic appearance. The degree of tissue involvement, the presence of immunoblasts, and the unusual phenotype of the T cell population may raise the suspicion of lymphoma. Features helpful in distinguishing ALPS from PTCL include the early age of onset, lack of lymph node effacement in biopsy specimens, polyclonal T cell expansion, and detection of pathogenic mutations by DNA sequencing. (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)  

Kikuchi-Fujimoto lymphadenitis — This is a self-limited reactive condition of uncertain etiology that most often involves the posterior cervical lymph nodes of young adult women. Kikuchi-Fujimoto lymphadenitis has histologic features that may be confused with T cell lymphoma [56]. Involved lymph nodes show patchy areas effaced by an infiltrate of large, activated CD8-positive cytotoxic T cells, associated with necrosis and karyorrhectic debris. Acute inflammatory cells, such as neutrophils, are absent from the lesions, which instead contain histiocytes of macrophage/monocyte lineage with crescentic nuclei. Key to recognition of Kikuchi-Fujimoto lymphadenitis is the clinical presentation (typically in posterior cervical lymph nodes of young adult women), the circumscribed and non-expansile nature of the nodal infiltrate, and detection of admixed CD123-positive plasmacytoid dendritic cells and histiocytes that express myeloperoxidase. (See "Kikuchi disease".)

Paracortical hyperplasia — Some cases of PTCL, NOS demonstrate a perifollicular (T-zone) growth pattern similar to that seen in benign paracortical hyperplasias, which may reflect a vigorous response to a viral infection, such as acute mononucleosis. The cells of paracortical hyperplasia may include a high proportion of large, rapidly dividing T immunoblasts that mimic the appearance of a lymphoma. Unlike PTCL, NOS, the T cells in benign hyperplasias have normal immunophenotypes and are typically polyclonal (by polymerase chain reaction [PCR]-based assays), and lack clonal T cell receptor (TCR) rearrangements that are seen in PTCL, NOS. (See "Infectious mononucleosis".)

Granulomatous lymphadenitis — Some cases of PTCL, NOS generate a granulomatous host response in involved tissues, with granulomas that are so numerous that they overshadow the neoplastic lymphoid cells in the background. The most important distinguishing factor is careful morphologic inspection of the lymphoid cells, which usually shows significant cytologic atypia in PTCL, NOS. Difficult cases can be distinguished by immunophenotyping and PCR-based assays for TCR rearrangements, which reveal a polyclonal pattern in granulomatous lymphadenitis.

PROGNOSIS — The clinical course of PTCL, NOS is aggressive, and relapses are common [6,11,57-60]. Disease stage at diagnosis and prognostic scoring systems correlate with survival in these patients (table 2) [61]. Stage for stage, compared with B cell non-Hodgkin lymphomas (NHL), patients with PTCL generally have a worse prognosis [7,16,58,62].

The International Prognostic Index (IPI) score and various T cell NHL-specific models have been applied to PTCL.

International Prognostic Index (IPI) — Prior to the routine use of rituximab for treatment of B cell NHL, a retrospective analysis compared the ability of the IPI (table 2) to predict outcomes in 288 patients with PTCL and 1595 patients with B cell NHL [62]. Compared with B cell NHL, cases of PTCL had more disseminated disease, B symptoms, and involvement of bone marrow or skin, but less bulky disease.

Patients with PTCL demonstrated [62]:

●Distribution of IPI scores - For all patients with PTCL, IPI scores of 0, 1, 2, and ≥3 were reported in 13, 17, 24, and 45 percent, respectively.

●Survival – Five-year overall survival (OS) for patients with PTCL varied with IPI score:

•IPI 0 – 82 percent

•IPI 1 - 73 percent

•IPI 2 – 58 percent

•IPI ≥3 - 35 percent

Other models — Other prognostic scoring system models have been proposed for T cell NHL, but they require further validation.

●Prognostic Index for PTCL, unspecified (PIT) – This model assigns one point for each of the following criteria (table 3) [63]:

•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 the PIT prognostic score and it demonstrated an association between increased score and decreased survival [63]. Patients with zero, one, two, or three to four of the adverse prognostic factors had five-year OS 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 OS and progression-free survival [64]. However, when applied to another cohort of 340 cases of PTCL, NOS, the PIT was not superior to the IPI for predicting survival [11].

●International peripheral T cell lymphoma Project score (IPTCLP) – The IPTCLP incorporates age (≤60 versus >60), ECOG performance score (≤1 versus >1), and platelet count (≤150K versus >150K) to classify patients into four groups [65]. When applied to 121 patients with PTCL, patients who had zero, one, two, or three risk factors demonstrated five-year OS 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 GATA3 or GATA3 target genes [22,42,43,64,66-69].

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

●Description – Peripheral T cell lymphoma (PTCL), not otherwise specified (NOS) is a heterogeneous group of predominantly nodal T cell lymphomas that generally present with lymphadenopathy, with or without extranodal involvement. PTCL must be distinguished from other specifically-defined subtypes of PTCL.

●Epidemiology – PTCL, NOS is the most common type of PTCL in Western countries, accounting for approximately one-third of cases. The incidence varies geographically, with the highest incidence found in Asia. (See 'Epidemiology' above.)

●Clinical presentation – 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.)

●Pathologic features

•Histology – Microscopy usually demonstrates a non-specific mixture of small, intermediate, and large atypical lymphoid cells (picture 2) that may be associated with reactive inflammatory cells. (See 'Histology' above.)

•Immunophenotype – Variable, but it must confirm the T cell origin of the tumor by expression of at least one pan-T cell antigen (ie, CD2, CD3, CD5, CD7). Many cases demonstrate an aberrant immunophenotype (eg, loss of a pan-T cell antigen; especially CD5 or CD7) and, rarely, may include expression of B cell antigens. (See 'Immunophenotype' above.)

•Genetic features – Approximately 90 percent of cases demonstrate cytogenetic abnormalities, but none is specific for PTCL, NOS. Most cases have clonal T cell receptor (TCR) gene rearrangements.

●Diagnosis – PTCL, NOS and other lymphomas may be suspected in individuals with lymphadenopathy, splenomegaly, constitutional symptoms, and findings related to organ infiltration.

•Specimen - Diagnosis requires an adequate specimen (ideally, an excisional or incisional biopsy) that permits characterization of morphology and immunophenotype. (See 'Biopsy specimen' above.)

•Criteria - PTCL, NOS is a diagnosis of exclusion, based on:

-Morphology - Variable mixtures of atypical small, intermediate, and large lymphoid cells with pleomorphic, irregular, vesicular, or hyperchromatic nuclei with prominent nucleoli and a high mitotic rate. (See 'Morphology' above.)

-Immunophenotype - Variable, but one or more pan-T antigens (ie, CD2, CD3, CD5, CD7) must be expressed. (See 'Immunophenotypic criteria' above.)

-Exclude other categories of PTCL – The tumor does not meet the criteria for other subtypes of T cell lymphoma (table 1), as described above. (See 'Exclude other categories of PTCL' above.)

Genetic studies are not required to diagnose or further classify PTCL, NOS, except to exclude other diagnoses. Although chromosomal and molecular abnormalities are common, none is specific for the diagnosis of PTCL, NOS.

●Differential diagnosis – The differential diagnosis of PTCL, NOS includes other T cell lymphomas, B cell lymphomas, and Hodgkin lymphomas and certain forms of reactive lymphoid hyperplasia, as discussed above. (See 'Differential diagnosis' above.)

●Prognosis – The clinical course of PTCL, NOS is aggressive, and relapses are common. The International Prognostic Index (IPI) (table 2) and other scoring systems can be used to estimate prognosis for patients with PTCL. (See 'Prognosis' above.)