Lymphoma classification update: T-cell lymphomas, Hodgkin lymphomas, and histiocytic/dendritic cell neoplasms

Abstract

Introduction

Lymphomas are classified based on the normal counterpart, or cell of origin, from which they arise. Because lymphocytes have physiologic immune functions that vary both by lineage and by stage of differentiation, the classification of lymphomas arising from these normal lymphoid populations is complex. Recent genomic data have contributed additional depth to this complexity.

Areas covered

Lymphoma classification follows the World Health Organization (WHO) system, which reflects international consensus and is based on pathological, genetic, and clinical factors. The present review focuses on the classification of T-cell lymphomas, Hodgkin lymphomas, and histiocytic and dendritic cell neoplasms, summarizing changes reflected in the 2016 revision to the WHO classification. These changes are critical to hematologists and other clinicians who care for patients with these disorders.

Expert commentary

Lymphoma classification is a continually evolving field that needs to be responsive to new clinical, pathological, and molecular understanding of lymphoid neoplasia. Among the entities covered in this review, the 2016 revisions in the WHO classification particularly impact T-cell lymphomas, including a new umbrella category of T-follicular helper cell-derived lymphomas and evolving recognition of indolent T-cell lymphomas and lymphoproliferative disorders.

1. Introduction

Lymphomas represent a heterogeneous group of lymphoid malignancies with varied patterns of clinical behavior and responses to treatment. The prognosis depends on the histologic type, clinical factors, and, more recently, molecular characteristics. Lymphomas are classified according to a system established by the World Health Organization (WHO), with the most recent fourth edition published in 2008 [1]. The WHO classification distinguishes lymphoid neoplasms derived from precursor lymphoid cells from those derived from mature lymphoid cells and further separates each group into neoplasms of B-cell or T-cell origin. For the most part, mature lymphoid neoplasms comprise the non-Hodgkin lymphomas (NHLs); Hodgkin lymphomas are considered separately. Tumors of mature histiocytic and dendritic cell (HDC) origin are not derived from lymphoid cells but often involve lymphoid tissue and historically have been discussed along with mature lymphoid neoplasms.

While the fourth edition of the WHO tumor monograph series is not yet completed for all tumor types, it was recognized that a revision of the lymphoid and other hematologic neoplasms was necessary, in part to reflect the rapidly accumulating wealth of genetic data that impact lymphoma biology, pathology, and clinical behavior. Although this ‘2016 revision’ has not been released in book form as of this writing, an overview was recently published [2]. The current review aims to summarize those facets of the revised classification that are anticipated to be most relevant to clinicians caring for lymphoma patients, here focusing on mature T-cell neoplasms, Hodgkin lymphoma, and HDC neoplasms.

2. Mature T-cell neoplasms

Approximately 10–15% of NHLs are of T-cell or natural killer (NK)-cell origin [3]. Tumors of mature (post-thymic or peripheral) T-cell origin are often referred to collectively as peripheral T-cell lymphomas (PTCLs) and are broadly separated into those with predominantly leukemic, extranodal, or nodal presentation. Studies in recent years have confirmed that most PTCL subtypes have a poorer prognosis than most B-cell NHL subtypes [4]. To date, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like combination chemotherapy still represents the standard approach to the treatment of most PTCLs [5]. However, except for anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), outcomes for most patients remain poor, with low response rates and short durations of response. Recent molecular advances have allowed further distinction of new subgroups that have both diagnostic and prognostic value. The WHO classification lists over 25 definite or provisional entities under the heading of mature T- and NK-cell neoplasms; however, as outlined above, this review summarizes those for which changes in the 2016 revision of the WHO classification are most important to clinicians (Tables 1 and 2).

Table 1.

Clinical significance of major 2016 World Health Organization changes for primarily nodal mature T-cell neoplasms.

Disease	Changes	Significance
ALK-negative ALCL	Upgraded from provisional to definite entity	Must be distinguished both from ALK-positive ALCL and from localized forms of disease, including pcALCL and BIA-ALCL
	Genetic subgroups recognized	Rearrangements involving DUSP22-IRF4 on 6p25.3 associated with favorable outcome
	BIA-ALCL	New provisional entity distinct from systemic ALK-negative ALCL occurring around breast implants Infiltrative form has more aggressive clinical behavior
T-cell lymphomas of TFH origin	Nodal T-cell lymphoma with TFH phenotype	New provisional entity for cases with TFH phenotype but not meeting criteria for AITL Previously would have been classified as PTCL, NOS Mutational spectrum overlapping other TFH entities
	Follicular T-cell lymphoma	New provisional entity for cases with TFH phenotype and follicular pattern of involvement Previously would have been classified as PTCL, NOS Mutational spectrum overlapping other TFH entities
PTCL, NOS	Remains a ‘wastebasket’ diagnosis for mature T-cell neoplasms not meeting criteria for other, more specific entities	Subgroups based on GATA3 and TBX21 expression may have clinical significance

AITL: angioimmunoblastic T-cell lymphoma; ALCL: anaplastic large-cell lymphoma; ALK: anaplastic lymphoma kinase; BIA-ALCL: breast implant-associated ALCL; pcALCL: primary cutaneous ALCL; PTCL: peripheral T-cell lymphoma; NOS: not otherwise specified; TFH: T-follicular helper.

Table 2.

Clinical significance of major 2016 World Health Organization changes for primarily extranodal and leukemic mature T-cell neoplasms.

Disease	Changes	Significance
T-cell lymphomas of the GI tract	EATL	Nomenclature to be used only for cases previously called type I EATL (usually associated with celiac disease)
	MEITL	New nomenclature for non-celiac disease-associated cases previously called type II EATL
	Indolent TLPD of the GI tract	New provisional entity with indolent clinical behavior Occasionally may progress
Cutaneous T-cell lymphomas	Primary cutaneous CD4-positive small/medium TLPD	Name changed from lymphoma to TLPD to reflect indolent behavior
	Primary cutaneous acral CD8-positive T-cell lymphoma	New provisional entity with indolent clinical behavior Most common involves ear
	Primary cutaneous γδ T-cell lymphoma	Excludes cases with γδ T-cell phenotype meeting criteria for other entities such as MF or LyP
EBV-positive NK-/T-cell neoplasms	Systemic EBV-positive T-cell lymphoma of childhood	Name changed from TLPD to lymphoma to reflect aggressive clinical behavior
	Hydroa vacciniforme-like lymphoproliferative disorder	Name changed from lymphoma to lymphoproliferative disorder to reflect wide spectrum of clinical behavior

EATL: enteropathy-associated T-cell lymphoma; GI: gastrointestinal; LyP: lymphomatoid papulosis; MEITL: monomorphic epitheliotropic intestinal T-cell lymphoma; MF: mycosis fungoides; TLPD: T-cell lymphoproliferative disorder; EBV: Epstein–Barr virus; NK: natural killer.

2.1. Anaplastic large-cell lymphoma

ALCLs represent a group of neoplasms of mature T-cell origin that express the lymphocyte activation marker, CD30 [6]. Broadly, ALCLs can be grouped based on the expression of the ALK (positive or negative) and by clinical presentation (systemic or localized). Localized forms of ALCL include primary cutaneous (pc) ALCL and breast implant-associated ALCL (BIA-ALCL).

ALK-positive ALCL is a systemic lymphoma characterized by recurrent chromosomal rearrangements involving the ALK gene on 2p23. These can be identified by genetic studies or, more commonly, by detecting the resultant ALK fusion protein by immunohistochemistry [7]. Most carry t(2;5)(p23;q25) translocations and express nucleophosmin (NPM)–ALK fusion proteins, leading to constitutive activation of ALK and downstream signaling pathways that regulate cell growth and survival [6–9]. Other ALK rearrangement partners have been identified in ALK-positive ALCL, including ATIC associated with the inv(2)(p23q35) inversion [10] and TRAF1 [11]. ALK-positive ALCL occurs mainly in children and young adults, has a male predominance (male to female ratio of 3), and typically presents with stage III to IV disease and systemic symptoms [4,12]. ALK-positive ALCL is associated with a better prognosis and overall survival (OS) rate than ALK-negative ALCL. The diagnostic criteria for ALK-positive ALCL remain unchanged from the 2008 WHO classification.

ALK-negative ALCL was recognized as a provisional entity distinct from ALK-positive ALCL in the 2008 WHO classification and has been upgraded to a definite entity in the 2016 classification [2]. As with ALK-positive ALCL, the term ‘ALK-negative ALCL’ refers to patients with systemic disease. ALK-negative ALCL mainly occurs in an older population with a median age of 43 years and presents with stage III to IV disease or extranodal involvement less frequently than ALK-positive ALCL [12]. Overall, ALK-negative ALCL has a prognosis inferior to that of ALK-positive ALCL, but recent data have shown that it is a genetically heterogeneous disease and that different genetic subgroups have distinct prognoses. Chromosomal rearrangements of the DUSP22-IRF4 locus on 6p25.3, most commonly associated with the t(6;7)(p25.3;q32.3) translocation, occur in 30% of cases and have a 5-year OS rate of 90%, similar to ALK-positive ALCL (Figure 1(a–c)) [13]. These cases have markedly downregulated the expression of DUSP22, which encodes a dual-specificity phosphatase with tumor suppressor functions [14–16]. In contrast, 8% of ALK-negative ALCLs have rearrangements of TP63, a TP53 homolog on 3q28, and demonstrate an aggressive clinical course and poor prognosis, with a 5-year OS rate of only 17% [13,17]. TP63 rearrangements most commonly involve the TBL1XR1 gene and form fusion proteins homologous to ΔNp63, a dominant-negative p63 isoform with oncogenic potential [18]. ALCLs that are negative for all three rearrangements (ALK, DUSP22, and TP63, or ‘triple-negative’ ALCLs) have a 42% 5-year OS rate [13]. Clinical trials are needed to answer the question of whether ALK-negative ALCLs with DUSP22 rearrangements ought to be treated less aggressively than the remaining ALK-negative ALCLs. Clinically available fluorescence in situ hybridization testing can identify DUSP22 or TP63 rearrangements in ALCL [13]; the 2016 WHO classification recognizes the prognostic significance of these rearrangements, but currently does not require this testing in the diagnosis of ALK-negative ALCL [2].

Figure 1.

Systemic and localized ALK-negative anaplastic large cell lymphomas. (a) Systemic ALK-negative anaplastic large cell lymphoma. H&E stain of a lymph node section shows sheets of neoplastic cells. (b) The tumor cells stain strongly and uniformly for CD30 by immunohistochemistry. (c) Fluorescence in situ hybridization showed this case to have a DUSP22 rearrangement, a finding that has been associated with favorable prognosis. The image shows a single tumor cell nucleus (blue). Hybridization with red and green breakapart probes flanking the DUSP22-IRF4 locus on 6p25.3 show one normal fusion signal (f) and abnormal separation of the red and green signals corresponding to the other allele (arrows), indicating a chromosomal rearrangement. (d) Breast implant-associated anaplastic large cell lymphoma involving the seroma cavity and fibrous capsule surrounding a breast implant. H&E stain shows clusters of cells that have pleomorphic nuclear features (inset; high magnification). Full color available online.

Interestingly, activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway has been identified in both ALK-positive ALCL and ALK-negative ALCL [19]. This finding may suggest a common signaling pathway underlying the pathogenesis of most or all ALCLs, provide a molecular basis for the morphological similarities among these entities, and represent a candidate therapeutic target [2,19].

BIA-ALCL has been emerged as a clinically distinct form of ALCL in recent years and now is included as a provisional entity. The disease was first described in 1997. A retrospective study of 19 BIA-ALCLs showed a median age of 61 years and a median interval of 9 years between the placement of the breast implants and the development of ALCL [20]. The neoplastic cells are CD30 positive and ALK negative [21]. Most cases have demonstrated T-cell antigen loss and nuclear expression of phosphorylated STAT3 [20,21]. BIA-ALCL may be confined to the fibrous capsule (the so-called ‘in situ’ form; Figure 1(d)) or may infiltrate adjacent tissues [20]. The in situ form of BIA-ALCL has an indolent clinical course and is associated with excellent event-free survival. The infiltrative form tends to have a more aggressive clinical course [20]. Complete surgical excision is critical to achieve optimal outcomes in patients with BIA-ALCL [22]. To date, it remains unclear whether additional treatment modalities beyond capsulectomy are of benefit; in one of the largest retrospective studies [23], the addition of chemotherapy was not associated with a statistically significant improvement in progression-free survival (PFS) or OS. However, patients with masses had PFS and OS rates inferior to patients without masses (e.g. 5-year OS rates of 75% versus 100%).

pcALCL is a distinct entity classified under the primary cutaneous CD30-positive T-cell lymphoproliferative disorders (TLPDs), which also include lymphomatoid papulosis (LyP) and cases borderline between LyP and pcALCL. pcALCL initially presents in the skin and must be distinguished from systemic ALK-negative ALCL that involves the skin secondarily by history, physical examination, and staging procedures. Diagnostic criteria for pcALCL remain unchanged from the 2008 WHO classification. Clinically, pcALCL behaves indolently, with a 5-year cumulative risk of progression to systemic ALCL of 14% based on the British Columbia Cancer Agency experience [24]. In this retrospective study, the 5-year disease-specific survival and OS were 86% and 75%, respectively. Patients with limited stage disease had excellent outcomes following treatment with radiation therapy alone.

LyP is an indolent TLPD with a spectrum of pathologic variants. While these variants are recognized by the WHO and should be specified when possible, they have similar clinical behavior, and their major significance relates to the differential diagnosis with other, more aggressive entities. In one of the largest reported retrospective studies of LyP, histologic variant did not affect prognosis, though patients with LyP type D were less likely to be associated with other type of lymphoma [25]. Interestingly, subsets of both LyP and pcALCL carry the same DUSP22 rearrangements seen in systemic ALK-negative ALCL [26,27].

2.2. T-cell lymphomas of T-follicular helper origin

Angioimmunoblastic T-cell lymphoma (AITL) is the classic form of T-cell lymphoma of T-follicular helper (TFH) origin, with diagnostic criteria that remain essentially unchanged from the 2008 WHO classification. AITL is one of the most common mature T-cell neoplasms and is an aggressive disease characterized by lymphadenopathy, systemic symptoms, and often immune manifestations such as hypergammaglobulinemia [4]. Pathologically, there is a polymorphic immune infiltrate in lymph node specimens, composed not only of tumor cells but also of a rich microenvironment containing small reactive lymphocytes, histiocytes, eosinophils, expanded follicular den-dritic cell meshworks, prominent endothelial venules, and Epstein–Barr virus (EBV)-positive large B immunoblasts [28]. The tumor cells express TFH cell markers, which may include CD10 and CD279 (PD-1, PDCD1), CXCL13, BCL6, CD40L, and NFATC1 [28–30].

The 2016 WHO classification includes two additional provisional entities representing neoplasms of TFH origin [2]. Nodal T-cell lymphomas with a TFH phenotype represent T-cell lymphomas that have a TFH phenotype but do not meet other criteria for AITL, while follicular T-cell lymphoma represents a T-cell lymphoma primarily involving the follicles, which morphologically may resemble follicular lymphoma of B-cell origin. Cases in both of these provisional categories previously would have been classified as PTCL, not otherwise specified (PTCL, NOS; see below). While they are kept distinct from AITL, they are included in the umbrella category of T-cell lymphomas of TFH origin not only because of their phenotype but also because of common genetic findings among these entities, including recurrent somatic mutations of TET2, RHOA, IDH2, CD28, and DNMT3A, as well as fusions of ITK-SYK and CD28-CTLA4 [31,32]. In the era of individualized medicine, these findings will likely lead to trials of epigenetic modifiers and/or immunotherapy. Of note, TET2 mutations are associated with advanced-stage disease, high international prognostic index scores, and a shorter PFS [33]. Typically, AITLis managed aggressively, similar to most other PTCLs. A trial of less-aggressive therapy (e.g. corticosteroids or cyclosporine) can be attempted in older patients with comorbidities but is not standard of care.

The B cells in the microenvironment of AITL and related neoplasms may give rise to concurrent, abnormal B-cell pro-liferations in about one-third of cases, which may progress into overt EBV-positive or EBV-negative B-cell lymphomas [34,35]. In some cases, the B cells in the background mimic Reed–Sternberg cells and may lead to a misdiagnosis of Hodgkin lymphoma if the neoplastic T-cell population is not recognized [36,37].

2.3. PTCL, not otherwise specified

PTCL, NOS comprises a heterogeneous group of mature T-cell lymphomas that do not meet diagnostic criteria for one of the more specific mature T-cell neoplasms; as such, it is a diagnosis of exclusion or a so-called ‘wastebasket’ diagnosis [1]. However, PTCL, NOS remains the most commonly diagnosed subtype of T-cell lymphoma, underscoring the need for increased understanding of this group of diseases. Despite the heterogeneous nature of PTCL, NOS, molecular subgroups with distinct features have been identified. Gene expression profiling studies have stratified PTCL, NOS based on expression of GATA3, TBX21, and cytotoxic markers [38]. One subgroup is characterized by high expression of GATA3 and its target genes, including CCR4, IL18RA, CXCR7, and IK. GATA3 is a T-cell transcription factor that binds to the DNA sequence, GATA, to regulate T helper cell differentiation via transcription of interleukin 4 (IL4) and IL13 and epigenetic modulation of IL10 [38–42]. A second subgroup is characterized by high expression of the T-box transcription factors TBX21 (Tbet) and eomesodermin (EOMES or Tbr2) and their target genes CXCR3, IL2RB, CCL3, and IFNG [38]. Both subgroups have generally poor clinical outcomes, but the GATA3 subgroup has an inferior prognosis, with a 5-year OS rate of 19% versus 38% for the TBX21 subgroup. However, within the TBX21 subgroup, expression of cytotoxic markers is associated with adverse outcomes. Whole-exome sequencing studies of PTCL, NOS have revealed marked heterogeneity but have identified recurrent mutations in genes involved in epigenetic regulation, DNA damage response, and Src signaling, including FYN, ATM, B2M, CD58, and RHOA [43].

2.4. T-cell lymphomas of the gastrointestinal tract

The nomenclature of enteropathy-associated T-cell lymphomas (EATLs) has changed in the 2016 WHO classification. In the past, these were classified as EATL type I and EATL type II, but only EATL type I was truly associated with enteropathy (celiac disease). In the 2016 classification, EATL refers only to the type I cases, whereas type II cases are renamed monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). In addition to the association with celiac disease, distinct genetic alterations have been identified in these two entities that further support this reclassification [44].

EATL is an extranodal T-cell NHL primarily affecting the gastrointestinal (GI) tract with an intraepithelial T-cell phenotype [1]. EATL typically has a highly aggressive clinical course and is associated with celiac disease, typically in northern European populations [45]. EATL is characterized by pleomorphic, anaplastic, or immunoblastic tumor cells, most commonly with an αβ T-cell receptor (TCR) phenotype, though γδ TCR cases exist [45]. EATL patients usually carry human leukocyte antigen (HLA)-DQ2 or DQ8, and the tumors often show copy number gains of 1q and 5q [1].

MEITL is not associated with celiac disease and is characterized by monomorphic small- to medium-sized tumor cells that express CD8, CD56, and megakaryocyte-associated tyrosine kinase [46]. MEITL is associated with frequent gains of the 8q24 locus involving the MYC oncogene [47,48]. The majority of MEITLs express γδ TCR, though there are αβ TCR variants [49]. Recurrent mutations in STAT5B have been identified in 37% of γδ MEITLs [44,50]. In a recent whole-exome sequencing study of 15 MEITLs, 93% of cases displayed loss-of-function SETD2 alterations with defective H3K36 trimethylation [51]. These findings were not observed in (type I) EATL, further highlighting the genomic differences between the two entities. Of note, preclinical data suggest that H3K36 trimethylation-deficient tumors may be particularly sensitive to WEE1 kinase inhibitors (e.g. AZD1775) [52].

Indolent TLPD of the GI tract is added as a new provisional entity in the 2016 WHO classification [2]. The whole GI tract is frequently involved and shows nondestructive infiltration by small, mature lymphoid cells [53]. The cells are commonly CD8 +/CD4−/CD56− and express the cytotoxic marker TIA1. Some cases may express CD4 (Figure 2). An NK-cell variant has been described but is not addressed specifically in the WHO classification. Most patients have an indolent course and do not need aggressive treatment, though occasional cases may progress [53].

Figure 2.

Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. (a) Low-power H&E image of fragments of mucosa from an endoscopic duodenal biopsy. (b) A higher power H&E image shows an infiltrate of small lymphocytes with bland cytological features (inset). (c) Nearly all the lymphocytes stain for CD4 by immunohistochemistry, and leave the intervening glands (g) relatively unaffected. (d) Staining for CD8 shows only occasional scattered cells. The T cells were shown to be clonal by molecular studies (not shown). This CD4-positive phenotype is less common than a CD8-positive phenotype in this disorder [53].

2.5. Cutaneous T-cell lymphomas

The most common CTCLs are mycosis fungoides (MF) and Sézary syndrome, for which diagnostic criteria have not changed significantly in the 2016 WHO classification, and the CD30-positive TLPDs discussed above in the section on ALCL.

The 2016 WHO classification has changed the nomenclature of primary cutaneous CD4-positive small/medium T-cell lymphoma to primary cutaneous CD4-positive small/medium TLPD to reflect the indolent clinical behavior of this entity. Clinically, patients typically present with a solitary cutaneous papule or nodule, especially on the upper part of the body, without a history of skin patches or plaques to suggest MF. The classic histopathologic changes include dermal infiltration by small lymphocytes with hyperchromatic nuclei, without significant epidermal, follicular, or adnexal involvement. Most cases have an indolent course and favorable outcome following excision, radiation, and/or other local therapies [2,54–56].

Primary cutaneous acral CD8-positive T-cell lymphoma is added as a new provisional entity in the 2016 WHO classification [2]. This entity is characterized by an indolent, slow-growing nodule localized to a single site, usually the ear, and can be managed conservatively with excision only, topical or intralesional steroids, or local radiotherapy [57]. No differences in outcomes were observed among these treatment modalities. Although primary cutaneous acral CD8-positive T-cell lymphoma has an indolent course, the histologic features of a dense, diffuse monomorphic infiltrate of medium-sized T cells throughout the dermis and subdermis can mimic higher-grade lymphomas. The indolent nature of these entities must be recognized to avoid overly aggressive management.

Primary cutaneous γδ T-cell lymphoma shows an EBV-negative, cytotoxic γδ T-cell phenotype and clonal rearrangements of the TCR receptor genes [58]. When the disease involves subcutaneous tissue, the process can resemble subcutaneous panniculitis-like T-cell lymphoma (SCPTCL) but is classified as a distinct entity because it tends to be clinically more aggressive than SCPTCL, which typically presents as cutaneous nodules in the trunk or extremities and has an αβ cytotoxic T-cell phenotype [2,59–61]. It should be noted that a γδ T-cell phenotype may be seen in cases meeting criteria for other WHO entities, including MF and LyP.

2.6. EBV-associated neoplasms of T and NK cells

The most common of these disorders is extranodal NK-/T-cell lymphoma, nasal type, though still relatively infrequent in western countries. Diagnostic criteria remain unchanged from the 2008 WHO classification.

Systemic EBV-positive T-cell lymphoma of childhood is characterized by a monoclonal proliferation of EBV-infected T cells with an activated cytotoxic phenotype (TIA1 positive) and a fulminant and aggressive clinical course, with survival measured in weeks due to multiple organ failure and sepsis [62]. The disease most often arises in the context of chronic active EBV infection in children, though it may follow acute EBV infection. The nomenclature of the entity was changed in the 2016 WHO classification from ‘lymphoproliferation’ to ‘lymphoma’ due to the aggressive clinical course [2].

In contrast, the name of hydroa vacciniforme-like lymphoproliferative disorder (HVLLD) was changed from ‘lymphoma’ to ‘lymphoproliferative disorder’ due to its wide spectrum of clinical behavior [2]. HVLLD is characterized by skin lesions, typically vesicles or vesicopapular eruptions, in sun-exposed areas and is associated with fever, lymphadenopathy, hepatosplenomegaly, and mosquito-bite hypersensitivity in some patients [63]. The abnormal cells in HVLLD may demonstrate an αβ T-cell, γδ T-cell, or NK-cell phenotype, and occasional patients progress to systemic lymphomas [63,64].

2.7. Leukemic mature T-cell neoplasms

T-cell large granular lymphocyte leukemia (T-LGL) is a rare leukemic TLPD characterized by clonal expansion of cytotoxic T cells and associated with autoimmune processes and immune-mediated cytopenias [65–67]. Most are of αβ T-cell origin, but some have a γδ T-cell phenotype. Koskela et al. have identified somatic STAT3 mutations in 40% of T-LGLs [68]. STAT3 mutations also are found in chronic lymphoproliferative disorders of NK cells, suggesting a possible common pathogenesis in these two clonal lymphoproliferations [69]. Less-frequent STAT5B mutations have also been identified in T-LGL [70]. Of note, somatic mutations in the STAT3 and STAT5B genes with activation of the corresponding proteins are also seen in a variety of γδ T-cell neoplasms, including hepatosplenic T-cell lymphomas, CTCLs, and MEITLs of γδ type [44,50,71]. The clinical relevance of these findings is yet to be established. STAT5B mutations may be associated with a more aggressive phenotype [66]. In a phase II study of immunosuppressive therapy with methotrexate in LGL, STAT3 Y640F mutations were associated with therapeutic response to methotrexate [72]. These findings will need to be reproduced; clinical trials with STAT3 inhibitors in LGL also should be explored.

3. Hodgkin lymphomas

While recent data indicate that most if not all Hodgkin lymphomas are of mature B-cell origin, they are classified separately from B-cell NHLs [1,2]. There are two main entities, classical Hodgkin lymphoma (CHL) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). These diseases share several important features that distinguish them from many NHLs. Clinically, they often present in young adults, primarily as nodal disease (most often with involvement of cervical lymph nodes). Pathologically, they are characterized by large neoplastic cells that represent the minority of the total cellular composition and are scattered in a rich background of non-neoplastic cells. Significant changes in the 2016 WHO revision that relate to Hodgkin lymphomas are summarized in Table 3.

Table 3.

Clinical significance of major 2016 World Health Organization changes for Hodgkin lymphomas and histiocytic/dendritic cell neoplasms.

Disease	Changes	Significance
Hodgkin lymphomas	LRCHL	Recognition of features intermediate between CHL and NLPHL
	NLPHL	Histologic pattern (A–F) should be specified when known; variant patterns associated with more aggressive behavior Cases with THRLBCL-like features should be called THRLBCL-like transformation of NLPHL to distinguish from true THRLBCL
HDC neoplasms	ECD	Should be distinguished from JXG based on clinical features Recurrent BRAF V600E mutations identified
	All subtypes	Occasional clonal relationship with underlying lymphoid neoplasm

CHL: classical Hodgkin lymphoma; ECD: Erdheim–Chester disease; HDC: histiocytic/dendritic cell; LRCHL: lymphocyte-rich CHL; NLPHL: nodular lymphocyte-predominant Hodgkin lymphoma; THRLBCL: T-cell/histiocyte-rich large B-cell lymphoma; JXG: juvenile xanthogranuloma.

3.1. Classical Hodgkin lymphoma

CHL is the more common of the two Hodgkin lymphoma entities and can be further divided into four histological subtypes: lymphocyte-rich CHL (LRCHL), nodular sclerosis CHL, mixed cellularity CHL, and lymphocyte-depleted CHL [1]. The classification and diagnostic criteria remain unchanged for CHL in the 2016 revision [2]. LRCHL is relatively infrequent, accounting for 3–5% of CHL; it typically presents with stage I or II disease and has a better prognosis than other CHL subtypes [1,73,74]. It shares some features with NLPHL morphologically and clinically, though it has a distinct immunophenotype and a lower frequency of relapse [73]. A comparison of markers of B-cell lineage, transcription factors, nuclear factor (NF)-κB signaling, and the T-cell microenvironment has demonstrated similarities among LRCHL, NLPHL, and CHL and has suggested that LRCHL has features intermediate between those of CHL and NLPHL [75].

3.2. Nodular lymphocyte predominant Hodgkin lymphoma

NLPHL is a rare entity that accounts for 3–5% of Hodgkin lymphomas [74,76]. The neoplastic cells of NLPHL are derived from germinal center B cells and express CD20, CD79a, CD75, BCL6, CD45, and J chain [77]. NLPHL typically occurs in young and middle-aged males and has an indolent clinical course [78]. NLPHL can be separated into nodular and diffuse histological patterns [77,79]. Most cases are nodular and show a mixed infiltrate of small reactive B cells with only occasional large, neoplastic ‘lymphocyte predominant’ cells, also referred to as ‘popcorn cells’ [1]. Fan et al. identified six distinct immunoarchitectural patterns of NLPHL, including classic nodular B-cell-rich (pattern A), serpiginous nodular (pattern B), nodular with prominent extranodular tumor cells (pattern C), T-cell-rich nodular (pattern D), diffuse T-cell-rich (pattern E), and diffuse B-cell-rich (p attern F) [80]. The variant patterns C through F are associated with advanced disease and a higher relapse rate at 5 years than the classic patterns A and B, and thus the pattern should be specified if possible in the pathology report [2,81].

Cases of NLPHL with diffuse architectural patterns must be distinguished from T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), a subtype of diffuse large B-cell lymphoma characterized by neoplastic CD20-positive B cells that usually constitute less than 10% of the infiltrate and are scattered among the non-neoplastic T cells with or without histiocytes [1]. THRLBCL usually presents with advanced clinical stage and is associated with a worse prognosis than NLPHL [82]. Nevertheless, NLPHL and THRLBCL share a number of features, and a recent study comparing the gene expression profiles of the diffuse T-cell-rich NLPHL (pattern E, also known as THRLBCL-like NLPHL) and THRLBCL revealed no significant differences [81,83]. Furthermore, classic NLPHL, THRLBCL-like NLPHL, and THRLBCL share common genetic alterations, including gains of 2p16.1 and losses of 2p11.2 and 9p11.2 [84]. It has been suggested that the diffuse patterns of NLPHL represent progression from NLPHL to THRLBCL or that these entities represent a spectrum of a single disease [81,83,84]. Cases of NLPHL transforming into THRLBCL or occurring synchronously with THRLBCL at a different site have been reported [2]. The 2008 WHO classification recommended describing NLPHL cases that progressed to a diffuse T-cell-rich pattern as ‘THRLBCL-like NLPHL’ to distinguish them from primary THRLBCL and indicated that at least focal presence of a typical NLPHL nodule be required for the diagnosis of NLPHL [1,2,80]. In the 2016 revision of the WHO classification, these cases are designated ‘THRLBCL-like transformation of NLPHL’ and have a more aggressive clinical course than typical NLPHL [2,85,86].

Since CD20 is expressed by the neoplastic cells in NLPHL, studies have looked at rituximab use as a single agent or in combination with chemotherapy. In one study [87], rituximab was studied as a single agent or single agent with a maintenance schedule in either newly diagnosed or relapsed cases of NLPHL. Despite an objective response rate of 100%, responses were not durable in most patients. Maintenance rituximab was associated with a trend towards longer PFS, but demonstrated no OS benefit. Choices of chemotherapy vary from CHL-like regimens with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to CHOP-like chemotherapy with the addition of rituximab. However, no randomized trial has compared these regimens side by side, and no standard of care for advanced NLPHL has yet been established.

4. HDC neoplasms

HDC neoplasms are derived from the mononuclear phagocytic system comprising dendritic cells and mononuclear phagocytes also referred to as histiocytes. Most tumors are of myeloid lineage, but some tumors such as follicular dendritic cell sarcoma have a mesenchymal origin [2]. Though these neoplasms are not lymphomas, historically they are often discussed with the mature lymphoid neoplasms as they have a mature state of differentiation and typically present in lymph nodes and other solid tissue sites, in contrast to many other myeloid tumors that are precursor neoplasms and often have a leukemic presentation. In addition, distinction of lymphoid and histiocytic neoplasms was difficult prior to immunophenotyping. Interestingly, HDC tumors may develop in patients with underlying mature or precursor B- or T-cell neoplasms and demonstrate clonal identity to the lymphoid component, including the same clonal immunoglobulin and/or TCR gene rearrangement, a phenomenon known as transdifferentiation [2,88–95]. Significant changes in the 2016 WHO revision that relate to HDC neoplasms are summarized in Table 3.

4.1. Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare, benign disorder characterized by a clonal proliferation of Langerhans cells expressing CD1a, langerin, and S100 [96]. The clinical presentation is widely variable, but the bones (>80%), skin (33%), and pituitary gland (25%) are frequently involved [96,97]. LCH with systemic involvement is referred to as Letterer–Siwe disease and presents with fever, hepatosplenomegaly, liver dysfunction, hematopoietic failure, and visceral involvement [98]. Genetics are discussed below.

4.2. Erdheim–Chester disease

Erdheim–Chester disease (ECD) is a rare, multi-organ, non-Langerhans cell histiocytic disorder that occurs predominantly in the 40–70-year-old age range with a male to female ratio of about 3:1 [96,99]. Pathologic changes include osteosclerotic lesions of the long bones with infiltration of foamy histiocytes and fibrosis (90% of patients), central nervous system involvement (20–50%), infiltration of the orbits (25%), retroperitoneal involvement (including the so-called ‘hairy kidney’; 30%), skin lesions (xanthelasma; 30%), cardiovascular involvement (with a ‘coated aorta’ appearance on imaging studies), and pulmonary changes (50%) [96,99–104]. The abnormal cells express CD68, CD163, and Factor XIIIa and are negative for CD1a, langerin, and S100 [96]. Patients typically have elevated levels of interferon-α, IL12, and monocyte chemotactic protein-1 and decreased levels of IL4 and IL7 [96,105]. The cells in ECD are identical to those in juvenile xanthogranuloma (JXG), but JXG usually does not present with multisystem involvement [96]. Positron emission tomography-computed tomography imaging is recommended for initial assessment of the overall disease burden in ECD due to its sensitivity for detecting extraosseous lesions [106]. Treatment with interferon-α has improved OS in ECD patients [107]. Anakinra, a recombinant IL1 receptor antagonist, also has shown efficacy [103].

Recent studies have identified a BRAF V600E mutation in over 50% of patients with ECD and LCH, suggesting a critical role of mitogen-activated protein (MAP) kinase signaling in the pathogenesis of both disorders [108,109]. Whole-exome and transcriptome sequencing has revealed recurrent mutations involving BRAF, ALK, and NTRK1, and in MAP2K1 and ARAF in non-Langerhans cell histiocytic tumors with wild-type BRAF, including ECD, JXG, and Rosai–Dorfman disease [96,110]. The BRAF inhibitor, vemurafenib, has resulted in dramatic clinical and radio-graphic responses in LCH and ECD and is recommended in refractory patients carrying the BRAF V600E mutation [111].

5. Expert commentary

Lymphoma classification is a continually evolving field that needs to be responsive to new clinical, pathological, and molecular understanding of lymphoid neoplasia. The 2016 revisions in the WHO classification of mature T-cell neoplasms, Hodgkin lymphomas, and HDC neoplasms include significant changes that impact the diagnosis, prognosis, and management of these diseases. The 2016 revision particularly impacts PTCLs and sees a reorganization of current categories and distinction of new provisional entities. The grouping of TFH-derived PTCLs into a new umbrella category represents a general example of how biologic and molecular features can help group diseases with similar characteristics, and a specific example of how discrete entities can be dissociated from the ‘wastebasket’ diagnosis of PTCL, NOS. Another major advance is the evolving recognition of indolent T-cell lymphomas and lymphoproliferative disorders, which are particularly important to distinguish, given the clinically aggressive nature of most PTCLs.

6. Five-year view

We anticipate that the future of T-cell lymphoma classification lies in molecular characterization of subgroups that will allow selection of appropriate targeted therapies and inclusion into clinical trials accordingly. These molecular tools are likely to include not only genomics but also other high-throughput technologies such as epigenomics, proteomics, and metabolomics. We expect these advances will continue to identify new entities with distinct clinical, pathological, and molecular features that will reclassify cases out of the heterogeneous and relatively common PTCL, NOS category. Advances in Hodgkin lymphoma are likely to arise from an increasing understanding of the relationship between the neoplastic cells and the rich microenvironment long recognized to be a critical component of this group of diseases. Finally, management of HDC neoplasms will be facilitated by ongoing genomic studies that are uncovering a spectrum of targetable alterations involving kinase signaling in this group of tumors.

Key issues.

• The 2016 revision of the World Health Organization classification of lymphoid neoplasms includes several critical changes in the classification of T-cell non-Hodgkin lymphomas, Hodgkin lymphomas, and histiocytic/dendritic cell neoplasms that have immediate impact on diagnosis, prognosis, management, and entry criteria for clinical research protocols.

• ALK-negative anaplastic large cell lymphoma has been upgraded to a definite entity, in which genetic markers may have prognostic significance; breast implant-associated cases are considered separately.

• T-cell lymphomas of T follicular helper cell origin share common clinical, pathological, and genetic features and are grouped in a new umbrella category containing 3 distinct entities.

• The classification of T-cell lymphomas of the gastrointestinal tract has been reorganized, and includes an indolent T-cell lymphoproliferative disorder as a new provisional entity.