Overview of T-cell Lymphomas

*Nagavalli Somasundaram and Soon Thye Lim*

## **Abstract**

T-cell lymphomas are a mixed bag of diseases with a similar origin but diverse in biology and behavior. This review aims to highlight the key changes to the WHO classification and summarize the therapeutic paradigm as of the time of writing in November 2018.

**Keywords:** T-cell lymphoma, transplant

## **1. Introduction**

T- and natural killer (NK)-cell lymphomas are a heterogeneous group of lymphoproliferative diseases that represent 10–15% of non-Hodgkin lymphomas (NHL). T-cell lymphomas in general have worse outcomes as compared to their B-cell counterparts. Over recent years, the understanding of the different subtypes of T-cell lymphoma has led to advances in management.

### **2. Background**

#### **2.1 WHO classification**

T- and NK-cell lymphomas can be subclassified according to nodal, extranodal, cutaneous, or leukemic subtypes based on the 2008 World Health Organization (WHO) classification of lymphoid malignancies (**Table 1**) [1]. The 2016 update of the WHO classification saw the addition of three provisional entities and changes in designation to five entities, reflecting the advancements in the understanding of this group of diseases [2, 3]. The major changes are highlighted below.

The update in the classification saw follicular T-cell lymphoma coming under the umbrella of angioimmunoblastic T-cell lymphoma (AITL), given the common genetic mutations such as *TET2*, *IDH2*, *DNMT3A*, *RHOA*, and *CD28* and fusions such as *ITK-SYK* and *CTLA4-CD28* nodal peripheral T-cell lymphoma (PTCL), previously classified under peripheral T-cell lymphoma, not otherwise specified (PTCL NOS) was reclassified under the AITL classification given the similar genetic landscape.

The diagnosis of PTCL NOS is made when a lymphoproliferative disorder is of the T-cell lineage without any distinctive features that fit into the subtypes. Two distinct molecular subgroups have been identified in PTCL NOS with differing clinical outcomes and prognosis. High expression of transcription factor *GATA3* was associated with worse clinical outcomes, while TBX2 expression enriched by IFNgamma and NfKB pathways was associated with better survival. These findings provide insight into a disease which has been a diagnosis of exclusion, with poor clinical outcomes and minimal advances in treatment.

**Table 1.** *Classification of T-cell lymphoma.*

The ALK-negative subtype of anaplastic large cell lymphoma (ALCL) has been identified as a distinct entity. The expression of *TNFRSF8*, *BATF*, and *TMOD1* differentiates ALK-negative ALCL from PTCL NOS. ALK-negative ALCL is a heterogeneous disease with a third harboring *DUSP22* rearrangement and another 8% having *TP63* rearrangements. The former has a 90% 5-year overall survival (OS) rate, mirroring the outcomes of its ALK-positive ALCL counterpart, while the latter is associated with a 5-year OS rate of 17%. The subset of ALK-negative ALCL which does not carry both the rearrangements has outcomes straddling in between these two extremes.

Breast implant-associated ALCL has been recognized as a provisional new entity—this is a unique variant in that the lymphomatous cells are confined to the seroma fluid surrounding the implant without capsular invasion. As such, surgical removal of the implant including the capsule is often curative, with systemic therapy being rarely indicated.

The 2008 classification included enteropathy-associated T-cell lymphoma (EATL) types 1 and 2 as part of the intestinal T-cell lymphoma spectrum. In the latest revision, this has been amended to EATL and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). EATL is a condition linked to coeliac disease and is more common among northern Europeans. MEITL, on the other hand, is a disease of Asians and Hispanics with no associations with coeliac disease. At a molecular level, EATL is predominantly characterized by T-cell alpha/beta receptor expression, while MEITL has predominantly T-cell gamma/delta receptors being expressed. The nuclear expression of megakaryocyte-associated tyrosine kinase, MYC amplification, and alterations in SETD2 and JAK STAT pathways are other genetic events characteristic of MEITL [4].

#### **2.2 Epidemiology**

PTCL NOS forms about 25% of T-cell lymphomas, followed by angioimmunoblastic T-cell lymphomas (18%), NK-/T-cell lymphomas (NKTL—10%), and adult T leukemia/lymphoma (9%) [5]. Geographic variation in the various subtypes

**9**

*Overview of T-cell Lymphomas*

*DOI: http://dx.doi.org/10.5772/intechopen.85058*

mia (ATLL) in the Asian population.

than other T-cell lymphoma subtypes.

or nodal disease [12].

**3.2 Workup and diagnosis**

outcomes [14].

**3. Clinical aspects**

**3.1 Clinical characteristics**

of T-cell lymphoma has been reported. The international T-cell lymphoma study reported rates of PTCL and NKTL to be 5–10% in Western countries and 10–20% in Asian countries. However, Au et al., in a study of 148 patients, reported similar frequencies of T-cell lymphomas in the Western and Asian populations [6]. This was supported by another study analyzing the differences between PTCL and NKTL [7]. The perceived difference in the disparate frequencies of these diseases may have been contributed by a higher incidence of NKTL and adult T-cell lymphoma/leuke-

PTCL NOS is a disease of older adults with a median age of 60. It often presents at advanced stages with both nodal and extranodal sites of disease, with cutaneous and bone marrow involvement being the most common extranodal sites [5, 8]. Angioimmunoblastic T-cell lymphoma (AITL) is a multifaceted disease with a spectrum of clinical presentations, from fairly indolent disease to aggressive presentations. Similar to PTCL NOS, it is also a disease of older adults. Patients often present in advanced stages with B symptoms being the most common clinical manifestation. Bone marrow, liver, spleen, and skin involvements are common in this disease [9]. Immune-related phenomena such as hemolytic anemia, hypergam-

Anaplastic large cell lymphomas (ALCL) are CD30-positive T-cell lymphoproliferative disorders with about half having ALK gene rearrangement (ALK + ALCL). The ALK-positive variant occurs in young adults with a median age of 30, while the ALK-negative ALCL is a disease of older adults. Systemic ALCLs have a varying clinical course and prognosis compared to their cutaneous counterparts, with the latter having an indolent course of disease with long-term survival in the range of 85–95% [11]. Central nervous system involvement is seen more commonly in ALCL

Extranodal NK-/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are the different subtypes of NKTL. NKTL commonly involves the nasal cavity and the upper aerodigestive tract. While localized disease is often treated with curative intent, advanced disease is invariably fatal. A small proportion of advanced NKTL patients can present with hemophagocytic syndrome resulting in high fevers, cytopenias, coagulopathy, abnormal liver function tests, and very high ferritin levels. Adult T-cell leukemia/lymphoma is a disease of adolescents and young adults. Extensive marrow involvement defines the leukemic variant of this disease, while the lymphoma variant has less than 20% marrow involvement. This is a highly aggressive disease with common presentations including bulky mediastinal masses

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of disease, with mycosis fungoides and Sezary syndrome being the most common subtypes. The incidence of the various subtypes often increases with age [13]. CTCLs are generally indolent diseases, but large cell transformation is generally associated with poor

Workup of T-cell lymphomas involves a complete history and physical examination followed by routine laboratory evaluation including full blood count, assessment

maglobulinemia, and positive Coombs test are associated with AITL [10].

#### *Overview of T-cell Lymphomas DOI: http://dx.doi.org/10.5772/intechopen.85058*

of T-cell lymphoma has been reported. The international T-cell lymphoma study reported rates of PTCL and NKTL to be 5–10% in Western countries and 10–20% in Asian countries. However, Au et al., in a study of 148 patients, reported similar frequencies of T-cell lymphomas in the Western and Asian populations [6]. This was supported by another study analyzing the differences between PTCL and NKTL [7]. The perceived difference in the disparate frequencies of these diseases may have been contributed by a higher incidence of NKTL and adult T-cell lymphoma/leukemia (ATLL) in the Asian population.

## **3. Clinical aspects**

*Peripheral T-cell Lymphomas*

The ALK-negative subtype of anaplastic large cell lymphoma (ALCL) has been identified as a distinct entity. The expression of *TNFRSF8*, *BATF*, and *TMOD1* differentiates ALK-negative ALCL from PTCL NOS. ALK-negative ALCL is a heterogeneous disease with a third harboring *DUSP22* rearrangement and another 8% having *TP63* rearrangements. The former has a 90% 5-year overall survival (OS) rate, mirroring the outcomes of its ALK-positive ALCL counterpart, while the latter is associated with a 5-year OS rate of 17%. The subset of ALK-negative ALCL which does not carry both

the rearrangements has outcomes straddling in between these two extremes. Breast implant-associated ALCL has been recognized as a provisional new entity—this is a unique variant in that the lymphomatous cells are confined to the seroma fluid surrounding the implant without capsular invasion. As such, surgical removal of the implant including the capsule is often curative, with systemic

The 2008 classification included enteropathy-associated T-cell lymphoma (EATL) types 1 and 2 as part of the intestinal T-cell lymphoma spectrum. In the latest revision, this has been amended to EATL and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). EATL is a condition linked to coeliac disease and is more common among northern Europeans. MEITL, on the other hand, is a disease of Asians and Hispanics with no associations with coeliac disease. At a molecular level, EATL is predominantly characterized by T-cell alpha/beta receptor expression, while MEITL has predominantly T-cell gamma/delta receptors being expressed. The nuclear expression of megakaryocyte-associated tyrosine kinase, MYC amplification, and alterations in SETD2 and JAK STAT pathways are other

PTCL NOS forms about 25% of T-cell lymphomas, followed by angioimmunoblastic T-cell lymphomas (18%), NK-/T-cell lymphomas (NKTL—10%), and adult T leukemia/lymphoma (9%) [5]. Geographic variation in the various subtypes

therapy being rarely indicated.

**Table 1.**

*Classification of T-cell lymphoma.*

genetic events characteristic of MEITL [4].

**8**

**2.2 Epidemiology**

#### **3.1 Clinical characteristics**

PTCL NOS is a disease of older adults with a median age of 60. It often presents at advanced stages with both nodal and extranodal sites of disease, with cutaneous and bone marrow involvement being the most common extranodal sites [5, 8].

Angioimmunoblastic T-cell lymphoma (AITL) is a multifaceted disease with a spectrum of clinical presentations, from fairly indolent disease to aggressive presentations. Similar to PTCL NOS, it is also a disease of older adults. Patients often present in advanced stages with B symptoms being the most common clinical manifestation. Bone marrow, liver, spleen, and skin involvements are common in this disease [9]. Immune-related phenomena such as hemolytic anemia, hypergammaglobulinemia, and positive Coombs test are associated with AITL [10].

Anaplastic large cell lymphomas (ALCL) are CD30-positive T-cell lymphoproliferative disorders with about half having ALK gene rearrangement (ALK + ALCL). The ALK-positive variant occurs in young adults with a median age of 30, while the ALK-negative ALCL is a disease of older adults. Systemic ALCLs have a varying clinical course and prognosis compared to their cutaneous counterparts, with the latter having an indolent course of disease with long-term survival in the range of 85–95% [11]. Central nervous system involvement is seen more commonly in ALCL than other T-cell lymphoma subtypes.

Extranodal NK-/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are the different subtypes of NKTL. NKTL commonly involves the nasal cavity and the upper aerodigestive tract. While localized disease is often treated with curative intent, advanced disease is invariably fatal. A small proportion of advanced NKTL patients can present with hemophagocytic syndrome resulting in high fevers, cytopenias, coagulopathy, abnormal liver function tests, and very high ferritin levels.

Adult T-cell leukemia/lymphoma is a disease of adolescents and young adults. Extensive marrow involvement defines the leukemic variant of this disease, while the lymphoma variant has less than 20% marrow involvement. This is a highly aggressive disease with common presentations including bulky mediastinal masses or nodal disease [12].

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of disease, with mycosis fungoides and Sezary syndrome being the most common subtypes. The incidence of the various subtypes often increases with age [13]. CTCLs are generally indolent diseases, but large cell transformation is generally associated with poor outcomes [14].

#### **3.2 Workup and diagnosis**

Workup of T-cell lymphomas involves a complete history and physical examination followed by routine laboratory evaluation including full blood count, assessment of end-organ function, lactate dehydrogenase levels, and screening for human immunodeficiency virus, hepatitis B and C. Epstein-Barr virus (EBV) DNA testing using EBV PCR can be considered in EBV-positive tumors. Plasma EBV detection can serve as a marker to monitor disease response and as a prognostic factor in these settings [15]. Staging evaluations include radiological imaging and bone marrow biopsy [18]. Fluorodeoxyglucose positron emission tomography combined with computer tomography (PET CT) is gaining an increasing role in the initial staging of T-cell lymphomas. Given the high propensity for extranodal involvement, some of which (e.g., cutaneous involvement) may not be well demarcated on CT, PET CT may be useful as an initial staging modality. A retrospective study demonstrated that almost a third of the patients in the study had additional sites of disease picked up on PET CT beyond conventional CT imaging [16]. In NKTL, PET CT has been established as a standard staging investigation given its high sensitivity and specificity [17].

The diagnosis of T-cell lymphomas should ideally be made by a hematopathologist. An excisional biopsy is recommended whenever possible in order to ensure availability of adequate tissue sample for histopathological analysis. According to the WHO classification in 2008, the diagnosis of PTCL requires the integration of clinical, pathological, immunohistochemical, and molecular findings.

## **4. Management**

At present there is no standard of care available for management of T-cell lymphoma as a result of paucity of randomized controlled phase 3 trials. Anthracycline-based regimens such as cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) have been the backbone of treatment for many decades for most subtypes of T-cell lymphomas, with the exception of NKTL. The international T-cell lymphoma project, with a predominant European and Asian population, demonstrated that there was no survival benefit seen with an anthracycline-based regimen for PTCL NOS and AITL [5]. A subsequent retrospective study in a north American population showed 25 months improvement in survival with the use of an anthracycline-based regimen, even after controlling for confounding factors [18]. Nevertheless, unlike the B-cell counterparts, T-cell lymphomas in general have a poorer outcome, with 5-year overall survival being about 30%.

In NKTL, anthracycline-based regimens were abandoned early on with the discovery that NK cells have a high expression of multidrug-resistant P-glycoprotein. Hence, drugs that are transported by P-glycoproteins such as cyclophosphamide and doxorubicin become ineffective [19]. L-asparaginase is an enzyme that induces cytotoxicity to lymphoma/leukemic cells by catalyzing the hydrolysis of L-asparagine, thereby resulting in its depletion. This drug has been demonstrated to have significant in vitro activity against NK cells [20] and hence has been incorporated into the treatment regimens. Hence, in advanced NKTL, L-asparaginase-based multiagent chemotherapy has been adopted as first-line treatment.

### **4.1 Strategies to improve first-line treatment**

#### *4.1.1 Intensive chemotherapy*

Multiple strategies have been explored in order to overcome the poor treatment outcomes in T-cell lymphomas. A retrospective study by MD Anderson group demonstrated that more intensive regimens such as HyperCVAD and HyperCHOP did

**11**

*Overview of T-cell Lymphomas*

six cycles of CHOP [23].

*4.1.2 Addition of etoposide*

ing the NHL B2 trial.

from the analysis [26].

a corresponding survival benefit [27].

as toxicity can be minimized.

explored in T-cell lymphomas.

between the ALK-positive and negative subtypes [28].

**4.2 Role of upfront autologous transplant as consolidation**

outcomes in T-cell lymphomas.

*DOI: http://dx.doi.org/10.5772/intechopen.85058*

not fare better than conventional CHOP in non-ALCL T-cell lymphomas. The 3-year overall survival was 49% in the intensive treatment group as compared to 43% in

The GOELAMS-LTP95 was a phase 3 randomized trial that compared alternating cycles of VIP and rABVD (etoposide, ifosfamide, cisplatin—VIP; reinforced adriamycin, bleomycin, vinblastine, dacarbazine—rABVD) against CHOP for non-cutaneous T-cell lymphomas. There was no significant difference in the 2-year

Gemcitabine, cisplatin, and methylprednisolone were compared to CHOP in the treatment of T-cell lymphomas in the first-line setting in a phase 2 trial. This CHEMO-T trial did not show any improvements in complete response rates, progression-free or overall survival rates between four cycles of GEM-P and

Hence, intensifying first-line chemotherapy as a strategy has not improved

The NHL B1 and B2 studies were designed to answer the questions of whether addition of etoposide to CHOP or increasing dose intensity of CHOP will improve outcomes in patients with aggressive lymphomas. T-cell lymphoma patients formed 13.7 and 5.8% of the study populations in NHL B1 [24] and B2 [25] studies, respectively. In young patients, addition of etoposide improved event-free survival by about 10%, but this did not translate into improvement in overall survival. In older patients, the addition of etoposide did not improve progression-free or overall survival compared to CHOP 14 which became the German standard of care follow-

A retrospective review of patients treated in trials designed by the German non-Hodgkin lymphoma study group showed an improvement in 3-year event-free survival (EFS) from 51 to 75.1% (p = 0.03). However, this difference in EFS was predominantly contributed by the ALK-positive ALCL—the EFS in this subgroup improved markedly from 57.1 to 91.2% with the addition of etoposide. The difference in EFS was no longer statistically significant when this group was removed

Similar results were noted in a retrospective study by a Swedish group which analyzed 755 patients with T-cell lymphoma. Improvement in EFS was seen without

A large retrospective study of 1933 Korean patients with T-cell lymphomas concluded that addition of etoposide had no progression-free or overall survival benefit, even in younger patients with good performance status. About 17% of the study population consisted of ALCL patients, but there was no differentiation

In summary, the benefit of etoposide comes through predominantly in the ALK-positive ALCL group. For the rest of T-cell lymphomas, etoposide is likely, and active agent and addition of this drug in younger patients remain an option, as long

The PARMA study established the role of high-dose chemotherapy and autologous peripheral stem cell transplant (HDC and APSCT) in relapsed refractory B-cell lymphomas. Given the poor outcomes of T-cell lymphomas, this option was

the CHOP group, and this was not statistically significant [21].

event-free survival, which was the primary endpoint of the study [22].

#### *Overview of T-cell Lymphomas DOI: http://dx.doi.org/10.5772/intechopen.85058*

*Peripheral T-cell Lymphomas*

**4. Management**

about 30%.

treatment.

*4.1.1 Intensive chemotherapy*

**4.1 Strategies to improve first-line treatment**

of end-organ function, lactate dehydrogenase levels, and screening for human immunodeficiency virus, hepatitis B and C. Epstein-Barr virus (EBV) DNA testing using EBV PCR can be considered in EBV-positive tumors. Plasma EBV detection can serve as a marker to monitor disease response and as a prognostic factor in these settings [15]. Staging evaluations include radiological imaging and bone marrow biopsy [18]. Fluorodeoxyglucose positron emission tomography combined with computer tomography (PET CT) is gaining an increasing role in the initial staging of T-cell lymphomas. Given the high propensity for extranodal involvement, some of which (e.g., cutaneous involvement) may not be well demarcated on CT, PET CT may be useful as an initial staging modality. A retrospective study demonstrated that almost a third of the patients in the study had additional sites of disease picked up on PET CT beyond conventional CT imaging [16]. In NKTL, PET CT has been established as a standard

staging investigation given its high sensitivity and specificity [17].

clinical, pathological, immunohistochemical, and molecular findings.

The diagnosis of T-cell lymphomas should ideally be made by a hematopathologist. An excisional biopsy is recommended whenever possible in order to ensure availability of adequate tissue sample for histopathological analysis. According to the WHO classification in 2008, the diagnosis of PTCL requires the integration of

At present there is no standard of care available for management of T-cell

lymphoma as a result of paucity of randomized controlled phase 3 trials. Anthracycline-based regimens such as cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) have been the backbone of treatment for many decades for most subtypes of T-cell lymphomas, with the exception of NKTL. The

international T-cell lymphoma project, with a predominant European and Asian population, demonstrated that there was no survival benefit seen with an anthracycline-based regimen for PTCL NOS and AITL [5]. A subsequent retrospective study in a north American population showed 25 months improvement in survival with the use of an anthracycline-based regimen, even after controlling for confounding factors [18]. Nevertheless, unlike the B-cell counterparts, T-cell lymphomas in general have a poorer outcome, with 5-year overall survival being

In NKTL, anthracycline-based regimens were abandoned early on with the discovery that NK cells have a high expression of multidrug-resistant P-glycoprotein. Hence, drugs that are transported by P-glycoproteins such as cyclophosphamide and doxorubicin become ineffective [19]. L-asparaginase is an enzyme that induces cytotoxicity to lymphoma/leukemic cells by catalyzing the hydrolysis of L-asparagine, thereby resulting in its depletion. This drug has been demonstrated to have significant in vitro activity against NK cells [20] and hence has been incorporated into the treatment regimens. Hence, in advanced NKTL, L-asparaginase-based multiagent chemotherapy has been adopted as first-line

Multiple strategies have been explored in order to overcome the poor treatment outcomes in T-cell lymphomas. A retrospective study by MD Anderson group demonstrated that more intensive regimens such as HyperCVAD and HyperCHOP did

**10**

not fare better than conventional CHOP in non-ALCL T-cell lymphomas. The 3-year overall survival was 49% in the intensive treatment group as compared to 43% in the CHOP group, and this was not statistically significant [21].

The GOELAMS-LTP95 was a phase 3 randomized trial that compared alternating cycles of VIP and rABVD (etoposide, ifosfamide, cisplatin—VIP; reinforced adriamycin, bleomycin, vinblastine, dacarbazine—rABVD) against CHOP for non-cutaneous T-cell lymphomas. There was no significant difference in the 2-year event-free survival, which was the primary endpoint of the study [22].

Gemcitabine, cisplatin, and methylprednisolone were compared to CHOP in the treatment of T-cell lymphomas in the first-line setting in a phase 2 trial. This CHEMO-T trial did not show any improvements in complete response rates, progression-free or overall survival rates between four cycles of GEM-P and six cycles of CHOP [23].

Hence, intensifying first-line chemotherapy as a strategy has not improved outcomes in T-cell lymphomas.

### *4.1.2 Addition of etoposide*

The NHL B1 and B2 studies were designed to answer the questions of whether addition of etoposide to CHOP or increasing dose intensity of CHOP will improve outcomes in patients with aggressive lymphomas. T-cell lymphoma patients formed 13.7 and 5.8% of the study populations in NHL B1 [24] and B2 [25] studies, respectively. In young patients, addition of etoposide improved event-free survival by about 10%, but this did not translate into improvement in overall survival. In older patients, the addition of etoposide did not improve progression-free or overall survival compared to CHOP 14 which became the German standard of care following the NHL B2 trial.

A retrospective review of patients treated in trials designed by the German non-Hodgkin lymphoma study group showed an improvement in 3-year event-free survival (EFS) from 51 to 75.1% (p = 0.03). However, this difference in EFS was predominantly contributed by the ALK-positive ALCL—the EFS in this subgroup improved markedly from 57.1 to 91.2% with the addition of etoposide. The difference in EFS was no longer statistically significant when this group was removed from the analysis [26].

Similar results were noted in a retrospective study by a Swedish group which analyzed 755 patients with T-cell lymphoma. Improvement in EFS was seen without a corresponding survival benefit [27].

A large retrospective study of 1933 Korean patients with T-cell lymphomas concluded that addition of etoposide had no progression-free or overall survival benefit, even in younger patients with good performance status. About 17% of the study population consisted of ALCL patients, but there was no differentiation between the ALK-positive and negative subtypes [28].

In summary, the benefit of etoposide comes through predominantly in the ALK-positive ALCL group. For the rest of T-cell lymphomas, etoposide is likely, and active agent and addition of this drug in younger patients remain an option, as long as toxicity can be minimized.

#### **4.2 Role of upfront autologous transplant as consolidation**

The PARMA study established the role of high-dose chemotherapy and autologous peripheral stem cell transplant (HDC and APSCT) in relapsed refractory B-cell lymphomas. Given the poor outcomes of T-cell lymphomas, this option was explored in T-cell lymphomas.

One of the earliest prospective studies addressing the role of upfront APSCT in T-cell lymphoma was reported by Corradini et al. [29]. This Italian study reported long-term outcomes of two prospective phase 2 studies of patients with T-cell lymphoma treated with upfront HDC and APSCT. Sixty-two patients with stage 2 to 4 T-cell lymphoma underwent two different conditioning regimens. Thirty percent of these patients had ALK-positive ALCL. Seventy-four percent of the patients underwent HDC and APSCT. Twelve-year overall survival and event-free survival with APSCT were 37 and 25%. ALK-positive ALCL patients had a significantly better survival than their other T-cell lymphoma counterparts. Achieving complete remission (CR) before APSCT was a strong predictor of improved survival in this study. Patients who achieved a CR before transplant had a 12-year DFS of 60% [29].

In another prospective single-arm study, 83 patients with PTCL, AITL, and ALK-negative ALCL as the predominant histologies were treated with 4–6 cycles of CHOP followed by HDC and APSCT. The 3-year OS and PFS were 48 and 36%, respectively. Eighty percent of patients relapsed within 24 months from APSCT [30].

The Nordic lymphoma group conducted a phase 2 prospective trial of 160 patients with T-cell lymphoma, to determine the outcomes of dose-dense chemotherapy followed by HDC and APSCT. Patients were treated with three cycles of CHOPE (cyclophosphamide, doxorubicin, vincristine, prednisolone, and etoposide) every 14 days. In patients older than 60, etoposide was omitted—hence patients received dose-dense CHOP. Those who had partial or complete responses (PR or CR) went on to receive three more cycles of the same chemotherapy regimen followed by HDC and APSCT. Of note, ALK-positive ALCL patients were excluded. PTCL NOS patients were 39% of the cohort, followed by AITL and ALK-negative ALCL, each consisting of 19%. About 70% of patients underwent HDC and APSCT. The 5-year OS and PFS were 51 and 44%, respectively. The ALK-negative ALCL group had the highest 5-year OS of 70%. Toxicities of the dose-dense regimen were however not insignificant. Grades 3 and 4 hematological and non-hematological toxicity rates were 86 and 45%, respectively, with a treatment-related mortality of 4% [31].

While these studies seem to suggest a better outcome with upfront HDC and APSCT, compared to historical controls, the lack of a randomized comparison between upfront HDC and APSCT and conventional chemotherapy alone makes it difficult to establish this as standard of care. Given the absence of randomized trials, HDC and APSCT in first clinical remission (CR1) has been incorporated into guidelines. However, recent data is emerging to suggest that patients in CR1 may actually not benefit from HDC and APSCT.

A retrospective review of 105 patients who received CHOP-based chemotherapy as first-line was done. About 52.1% of the study population were in CR1. About half of these patients underwent HDC and APSCT, whereas the other half were on surveillance. At 22 months, the median PFS of the surveillance group compared to the group that underwent transplant was 15.8 months vs. 12.8 months, but this was not statistically significant. The authors hence concluded that patients who are in CR1 following induction chemotherapy may not benefit from APSCT [32].

Our group did a retrospective analysis of 175 patients from Singapore, South Korea, and China. PTCL NOS patients formed 42% of the cohort. AITL and ALK-negative ALCL formed 33% and 22% of the cohort, respectively. About 92% of patients received anthracycline-based induction chemotherapy. However, only 18% of the cohort underwent upfront HDC and APSCT. Median PFS was 5.5 years for the entire population but OS was not reached. On multivariate analysis, age and advanced stage of disease were identified as poor prognostic factors. The use of anthracycline-based regimens as well as HDC and APSCT did not feature as significant factors affecting survival or progression-free survival outcomes, even in younger patients [33].

**13**

*Overview of T-cell Lymphomas*

*DOI: http://dx.doi.org/10.5772/intechopen.85058*

**4.3 Role of allogenic transplant in CR1**

**4.4 Relapsed or refractory disease**

survival [37, 38].

**4.5 Novel agents**

*4.5.1 Brentuximab vedotin*

These results were echoed in a multicenter retrospective study done in Europe. AITL was the most common subtype in this dataset (46%), compared to PTCL NOS (29%) and ALK-positive ALCL (25%). In order to eliminate selection bias in the retrospective analysis, multivariate proportional hazard model and propensity score matching model were both applied. Two-hundred sixty-nine patients were analyzed among whom half the patients had undergone HDC and APSCT at CR1 and the other half was under surveillance. Five-year PFS and OS were 45% and 60%, respectively, for the overall population. Consolidation APSCT at CR1 did not improve survival outcomes in this population. Once again, remission status (CR or

In summary, achieving a CR at the end of induction therapy is a crucial prognostic factor in determining outcomes in TCL. The role of upfront autologous transplant, especially in patients who have achieved CR1, remains to be defined.

Two prospective studies attempted to explore the role of allogenic transplant in first remission [35, 36]. In both the studies, about 39% of patients did not undergo transplant, predominantly due to early progression. In the Italian study, only a quarter of the patients who underwent transplant remained in CR at 44 months. Hence, allogenic transplant as consolidation therapy is not recommended.

In the relapsed setting, autologous or allogenic transplant remains as options following salvage chemotherapy to attain a response. The Center for International Blood and Marrow Transplant Research reported 3-year PFS and OS rates of 41 and 53%, respectively, for patients undergoing autologous transplant at first relapse. The rationale for allogenic transplant in lymphoma has been to harness the graft versus lymphoma effect. Three-year OS for myeloablative versus a non-myeloablative regimen was 31 and 50%, respectively. Once again, having a chemosensitive disease and having two lines of treatment or fewer were important prognostic factors for

Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a chimeric monoclonal antibody linked to an anti-tubulin agent, monomethyl auristatin E (MMAE). The monoclonal antibody targets CD30-expressing cells, and MMAE is released intracellularly to bind to tubulin. The binding of MMAE to tubulin disrupts the microtubule network, causing cell cycle arrest and apoptosis. Brentuximab vedotin is cell cycle phase-specific (G2/M phase). CD30 is uniformly expressed in anaplastic large cell lymphomas. In addition to that, about 43% of PTCL (excluding

A phase 2 study demonstrated a response rate of 41% when brentuximab was administered to CD30-positive T-cell lymphomas, at 1.8 mg/kg every 3 weeks. This study excluded ALCL patients. This was a considerable response given that 63% of patients were refractory to the most recent therapy prior to brentuximab. Interestingly,

A retrospective French study analyzed the effectiveness of brentuximab in 56 patients. Twenty-four patients had ALCL. Cutaneous lymphomas (72%) and

the degree of CD30 expression did not correlate with the responses [40].

ALL) has been estimated to have CD30 expression [39].

PR) at the end of induction featured as a significant prognostic factor [34].

#### *Overview of T-cell Lymphomas DOI: http://dx.doi.org/10.5772/intechopen.85058*

*Peripheral T-cell Lymphomas*

actually not benefit from HDC and APSCT.

One of the earliest prospective studies addressing the role of upfront APSCT in T-cell lymphoma was reported by Corradini et al. [29]. This Italian study reported long-term outcomes of two prospective phase 2 studies of patients with T-cell lymphoma treated with upfront HDC and APSCT. Sixty-two patients with stage 2 to 4 T-cell lymphoma underwent two different conditioning regimens. Thirty percent of these patients had ALK-positive ALCL. Seventy-four percent of the patients underwent HDC and APSCT. Twelve-year overall survival and event-free survival with APSCT were 37 and 25%. ALK-positive ALCL patients had a significantly better survival than their other T-cell lymphoma counterparts. Achieving complete remission (CR) before APSCT was a strong predictor of improved survival in this study. Patients who achieved a CR before transplant had a 12-year DFS of 60% [29]. In another prospective single-arm study, 83 patients with PTCL, AITL, and ALK-negative ALCL as the predominant histologies were treated with 4–6 cycles of CHOP followed by HDC and APSCT. The 3-year OS and PFS were 48 and 36%, respectively. Eighty percent of patients relapsed within 24 months from APSCT [30]. The Nordic lymphoma group conducted a phase 2 prospective trial of 160 patients with T-cell lymphoma, to determine the outcomes of dose-dense chemotherapy followed by HDC and APSCT. Patients were treated with three cycles of CHOPE (cyclophosphamide, doxorubicin, vincristine, prednisolone, and etoposide) every 14 days. In patients older than 60, etoposide was omitted—hence patients received dose-dense CHOP. Those who had partial or complete responses (PR or CR) went on to receive three more cycles of the same chemotherapy regimen followed by HDC and APSCT. Of note, ALK-positive ALCL patients were excluded. PTCL NOS patients were 39% of the cohort, followed by AITL and ALK-negative ALCL, each consisting of 19%. About 70% of patients underwent HDC and APSCT. The 5-year OS and PFS were 51 and 44%, respectively. The ALK-negative ALCL group had the highest 5-year OS of 70%. Toxicities of the dose-dense regimen were however not insignificant. Grades 3 and 4 hematological and non-hematological toxicity rates were 86 and 45%, respectively, with a treatment-related mortality of 4% [31]. While these studies seem to suggest a better outcome with upfront HDC and APSCT, compared to historical controls, the lack of a randomized comparison between upfront HDC and APSCT and conventional chemotherapy alone makes it difficult to establish this as standard of care. Given the absence of randomized trials, HDC and APSCT in first clinical remission (CR1) has been incorporated into guidelines. However, recent data is emerging to suggest that patients in CR1 may

A retrospective review of 105 patients who received CHOP-based chemotherapy

as first-line was done. About 52.1% of the study population were in CR1. About half of these patients underwent HDC and APSCT, whereas the other half were on surveillance. At 22 months, the median PFS of the surveillance group compared to the group that underwent transplant was 15.8 months vs. 12.8 months, but this was not statistically significant. The authors hence concluded that patients who are in CR1 following induction chemotherapy may not benefit from APSCT [32].

Our group did a retrospective analysis of 175 patients from Singapore, South Korea, and China. PTCL NOS patients formed 42% of the cohort. AITL and ALK-negative ALCL formed 33% and 22% of the cohort, respectively. About 92% of patients received anthracycline-based induction chemotherapy. However, only 18% of the cohort underwent upfront HDC and APSCT. Median PFS was 5.5 years for the entire population but OS was not reached. On multivariate analysis, age and advanced stage of disease were identified as poor prognostic factors. The use of anthracycline-based regimens as well as HDC and APSCT did not feature as significant factors affecting survival or progression-free survival outcomes, even in

**12**

younger patients [33].

These results were echoed in a multicenter retrospective study done in Europe. AITL was the most common subtype in this dataset (46%), compared to PTCL NOS (29%) and ALK-positive ALCL (25%). In order to eliminate selection bias in the retrospective analysis, multivariate proportional hazard model and propensity score matching model were both applied. Two-hundred sixty-nine patients were analyzed among whom half the patients had undergone HDC and APSCT at CR1 and the other half was under surveillance. Five-year PFS and OS were 45% and 60%, respectively, for the overall population. Consolidation APSCT at CR1 did not improve survival outcomes in this population. Once again, remission status (CR or PR) at the end of induction featured as a significant prognostic factor [34].

In summary, achieving a CR at the end of induction therapy is a crucial prognostic factor in determining outcomes in TCL. The role of upfront autologous transplant, especially in patients who have achieved CR1, remains to be defined.

## **4.3 Role of allogenic transplant in CR1**

Two prospective studies attempted to explore the role of allogenic transplant in first remission [35, 36]. In both the studies, about 39% of patients did not undergo transplant, predominantly due to early progression. In the Italian study, only a quarter of the patients who underwent transplant remained in CR at 44 months. Hence, allogenic transplant as consolidation therapy is not recommended.

#### **4.4 Relapsed or refractory disease**

In the relapsed setting, autologous or allogenic transplant remains as options following salvage chemotherapy to attain a response. The Center for International Blood and Marrow Transplant Research reported 3-year PFS and OS rates of 41 and 53%, respectively, for patients undergoing autologous transplant at first relapse. The rationale for allogenic transplant in lymphoma has been to harness the graft versus lymphoma effect. Three-year OS for myeloablative versus a non-myeloablative regimen was 31 and 50%, respectively. Once again, having a chemosensitive disease and having two lines of treatment or fewer were important prognostic factors for survival [37, 38].

## **4.5 Novel agents**

## *4.5.1 Brentuximab vedotin*

Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a chimeric monoclonal antibody linked to an anti-tubulin agent, monomethyl auristatin E (MMAE). The monoclonal antibody targets CD30-expressing cells, and MMAE is released intracellularly to bind to tubulin. The binding of MMAE to tubulin disrupts the microtubule network, causing cell cycle arrest and apoptosis. Brentuximab vedotin is cell cycle phase-specific (G2/M phase). CD30 is uniformly expressed in anaplastic large cell lymphomas. In addition to that, about 43% of PTCL (excluding ALL) has been estimated to have CD30 expression [39].

A phase 2 study demonstrated a response rate of 41% when brentuximab was administered to CD30-positive T-cell lymphomas, at 1.8 mg/kg every 3 weeks. This study excluded ALCL patients. This was a considerable response given that 63% of patients were refractory to the most recent therapy prior to brentuximab. Interestingly, the degree of CD30 expression did not correlate with the responses [40].

A retrospective French study analyzed the effectiveness of brentuximab in 56 patients. Twenty-four patients had ALCL. Cutaneous lymphomas (72%) and

#### *Peripheral T-cell Lymphomas*

ALCLs (62%) had better overall response rates than non-ALCL PTCLs (21%). Contrary to the study by Horwitz et al., this study reported a statistically significant improvement in PFS with stronger (>75%) expression of CD30 [41].

A prior study in JCO reported exceptional response rates of 86% with the use of brentuximab in relapsed refractory ALCL. The CR rates were 57% and median duration of response was 12.6 months. These excellent responses were demonstrated despite 62% of patients having primary refractory disease [42].

The ALCANZA trial was a phase 3 trial that compared brentuximab against physician choice treatment for patients with cutaneous T-cell lymphomas who have seen prior treatment. This study demonstrated that patients who had brentuximab had better objective global response rates (56.3%) than those who had physician choice treatment (12.5%). The endpoint of objective global response comprised of response in the skin, node, viscera, and blood, lasting for a minimum of 4 months. The median progression-free survival was 16.7 months vs. 3.5 months HR 0.27 (p < 0.0001). These results are certainly promising, especially given that this group of diseases has limited efficacious systemic treatment [43, 44].

The efficacy of brentuximab in the relapsed refractory settings has prompted the evaluation of this drug in the first-line setting. A phase 1 study explored the safety and efficacy of combining brentuximab with cyclophosphamide, doxorubicin, and prednisolone (BV CHP) in 26 treatment naïve PTCL patients. Patients received six cycles of BV CHP followed by BV maintenance for up to 10 cycles. Seventy-three percent of the study population consisted of ALCL. One hundred percent response rate with 50% continuing to remain in CR at 5 years was reported. The predominant toxicity was peripheral neuropathy which resolved in the majority. While the results are exciting, it is possible that the results were driven primarily by the ALCL population. A larger randomized study stratified by tumor subtypes will be important before this is adopted as the new standard of care [44].

Regardless, the promising efficacy of brentuximab, at least in the post first-line setting cannot be disregarded. This is generally a well-tolerated drug with predominant toxicities being peripheral neuropathy, myelosuppression, fatigue, and nausea.

#### *4.5.2 Pralatrexate*

Pralatrexate is a novel antifolate drug which inhibits dihydrofolate reductase enzyme, thereby inhibiting the conversion of dihydrofolate to tetrahydrofolate. Blocking this essential step in DNA and RNA synthesis results in cell cycle arrest. In addition, its high affinities for reduced folate carrier and folylpolyglutamate synthase are distinctive features that account for its superior activity compared to other drugs in the same class [45]. The early phase II-I-II study showed an overall response rate of 54% in TCL, compared to only 5% in B-cell lymphomas [46]. A weekly dose of 30 mg/m2 for 6 out of 7 weeks had a better toxicity profile than a dose of 135 mg/m2 given every other week. The PROPEL study which recruited 115 patients with TCL demonstrated an overall response rate of 29%. Eleven percent achieved CR. Of note, 5 out of 26 patients who were refractory to prior lines of therapy responded to this drug [47]. However, common toxicities of this drug include mucositis, fatigue, myelosuppression, and abnormal liver function tests.

#### *4.5.3 Romidepsin*

Romidepsin is predominantly a class 1 histone deacetylase inhibitor (HDAC). Through complex interactions, which remain to be fully understood, this drug disrupts chromatin structure and activates transcription factors. As a result, it mediates cell cycle arrest and cell death and increases transcription of tumor suppressor

**15**

provided the original work is properly cited.

1 National Cancer Center Singapore, Singapore

2 Duke-NUS Medical School, Singapore

*Overview of T-cell Lymphomas*

infections, fatigue, and nausea.

*4.5.4 Belinostat*

a dose of 1000 mg/m2

**5. Conclusion**

**Author details**

Nagavalli Somasundaram1

cal toxicities, nausea, and fatigue [50].

improve outcomes from these diseases.

*DOI: http://dx.doi.org/10.5772/intechopen.85058*

genes. In a pivotal phase 2 study, romidepsin was administered at 14 mg/m<sup>2</sup> on days 1 and 8 and 15 in a 28 days cycle, to patients with relapsed or refractory T-cell lymphoma. PTCL and AITL were the most common subtypes in the study. A 25% response rate was reported, with 15% achieving CR. Responses were also durable with median duration of response being 17 months [48]. Another phase 2 study by the NCI group reported 38% response rates with duration of response being 8.9 months [49]. The main toxicities in both these studies were cytopenias,

Belinostat is a pan-HDAC inhibitor which inhibits classes I, II, and IV HDAC. It facilitates apoptosis and cell cycle arrest in abnormal, transformed cells through complex interactions with cell cycle mechanisms. Based on a phase 2 trial which demonstrated 25% response rates in PTCL, the BELIEF (Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma) trial was conducted. This was a single-arm study where belinostat was administered as an intravenous infusion at

T-cell lymphomas. The study reported a modest objective response rate of 26% with duration of response of 8.3 months. Of note, AITL patients had a higher response rate of 46% than 23% in PTCL patients. The main toxicities were fever, hematologi-

T-cell lymphoma has evolved from being one disease to a mixed bag of multiple diseases, each of which is being understood at greater depths now, with the advent of technology and molecular biology. With a better understanding of the disease biologies, the therapeutic armamentarium needs to be developed further in order to

on days 1–5 Q21 days, to patients with relapsed or refractory

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

and Soon Thye Lim1,2\*

\*Address all correspondence to: lim.soon.thye@singhealth.com.sg

#### *Overview of T-cell Lymphomas DOI: http://dx.doi.org/10.5772/intechopen.85058*

genes. In a pivotal phase 2 study, romidepsin was administered at 14 mg/m<sup>2</sup> on days 1 and 8 and 15 in a 28 days cycle, to patients with relapsed or refractory T-cell lymphoma. PTCL and AITL were the most common subtypes in the study. A 25% response rate was reported, with 15% achieving CR. Responses were also durable with median duration of response being 17 months [48]. Another phase 2 study by the NCI group reported 38% response rates with duration of response being 8.9 months [49]. The main toxicities in both these studies were cytopenias, infections, fatigue, and nausea.

## *4.5.4 Belinostat*

*Peripheral T-cell Lymphomas*

ALCLs (62%) had better overall response rates than non-ALCL PTCLs (21%). Contrary to the study by Horwitz et al., this study reported a statistically significant

A prior study in JCO reported exceptional response rates of 86% with the use of brentuximab in relapsed refractory ALCL. The CR rates were 57% and median duration of response was 12.6 months. These excellent responses were demon-

The ALCANZA trial was a phase 3 trial that compared brentuximab against physician choice treatment for patients with cutaneous T-cell lymphomas who have seen prior treatment. This study demonstrated that patients who had brentuximab had better objective global response rates (56.3%) than those who had physician choice treatment (12.5%). The endpoint of objective global response comprised of response in the skin, node, viscera, and blood, lasting for a minimum of 4 months. The median progression-free survival was 16.7 months vs. 3.5 months HR 0.27 (p < 0.0001). These results are certainly promising, especially given that this group

The efficacy of brentuximab in the relapsed refractory settings has prompted the evaluation of this drug in the first-line setting. A phase 1 study explored the safety and efficacy of combining brentuximab with cyclophosphamide, doxorubicin, and prednisolone (BV CHP) in 26 treatment naïve PTCL patients. Patients received six cycles of BV CHP followed by BV maintenance for up to 10 cycles. Seventy-three percent of the study population consisted of ALCL. One hundred percent response rate with 50% continuing to remain in CR at 5 years was reported. The predominant toxicity was peripheral neuropathy which resolved in the majority. While the results are exciting, it is possible that the results were driven primarily by the ALCL population. A larger randomized study stratified by tumor subtypes

Regardless, the promising efficacy of brentuximab, at least in the post first-line setting cannot be disregarded. This is generally a well-tolerated drug with predominant toxicities being peripheral neuropathy, myelosuppression, fatigue, and nausea.

Pralatrexate is a novel antifolate drug which inhibits dihydrofolate reductase enzyme, thereby inhibiting the conversion of dihydrofolate to tetrahydrofolate. Blocking this essential step in DNA and RNA synthesis results in cell cycle arrest. In addition, its high affinities for reduced folate carrier and folylpolyglutamate synthase are distinctive features that account for its superior activity compared to other drugs in the same class [45]. The early phase II-I-II study showed an overall response rate of 54% in TCL, compared to only 5% in B-cell lymphomas [46]. A weekly dose of

for 6 out of 7 weeks had a better toxicity profile than a dose of

with TCL demonstrated an overall response rate of 29%. Eleven percent achieved CR. Of note, 5 out of 26 patients who were refractory to prior lines of therapy responded to this drug [47]. However, common toxicities of this drug include mucositis, fatigue, myelosuppression, and abnormal liver function tests.

Romidepsin is predominantly a class 1 histone deacetylase inhibitor (HDAC). Through complex interactions, which remain to be fully understood, this drug disrupts chromatin structure and activates transcription factors. As a result, it mediates cell cycle arrest and cell death and increases transcription of tumor suppressor

given every other week. The PROPEL study which recruited 115 patients

improvement in PFS with stronger (>75%) expression of CD30 [41].

strated despite 62% of patients having primary refractory disease [42].

of diseases has limited efficacious systemic treatment [43, 44].

will be important before this is adopted as the new standard of care [44].

**14**

*4.5.2 Pralatrexate*

30 mg/m2

135 mg/m2

*4.5.3 Romidepsin*

Belinostat is a pan-HDAC inhibitor which inhibits classes I, II, and IV HDAC. It facilitates apoptosis and cell cycle arrest in abnormal, transformed cells through complex interactions with cell cycle mechanisms. Based on a phase 2 trial which demonstrated 25% response rates in PTCL, the BELIEF (Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma) trial was conducted. This was a single-arm study where belinostat was administered as an intravenous infusion at a dose of 1000 mg/m2 on days 1–5 Q21 days, to patients with relapsed or refractory T-cell lymphomas. The study reported a modest objective response rate of 26% with duration of response of 8.3 months. Of note, AITL patients had a higher response rate of 46% than 23% in PTCL patients. The main toxicities were fever, hematological toxicities, nausea, and fatigue [50].

## **5. Conclusion**

T-cell lymphoma has evolved from being one disease to a mixed bag of multiple diseases, each of which is being understood at greater depths now, with the advent of technology and molecular biology. With a better understanding of the disease biologies, the therapeutic armamentarium needs to be developed further in order to improve outcomes from these diseases.

## **Author details**

Nagavalli Somasundaram1 and Soon Thye Lim1,2\*


\*Address all correspondence to: lim.soon.thye@singhealth.com.sg

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**16**

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*Peripheral T-cell Lymphomas*

2016;**127**(20):2375-2390

(Suppl 1):97-103

2010;**2010**:624040

2008;**26**(25):4124-4130

[1] Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: Evolving concepts and practical applications. Blood. 2011;**117**(19):5019-5032

[8] Weisenburger DD, Savage KJ, Harris NL, Gascoyne RD, Jaffe ES, MacLennan KA, et al. Peripheral T-cell lymphoma, not otherwise specified: A report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood.

2011;**117**(12):3402-3408

[9] Lunning MA, Vose JM.

2017;**129**(9):1095-1102

2013;**31**(2):240-246

2003;**49**(6):1049-1058

2017;**92**(10):1085-1102

2000;**18**(15):2908-2925

Angioimmunoblastic T-cell lymphoma: The many-faced lymphoma. Blood.

[10] Federico M, Rudiger T, Bellei M, Nathwani BN, Luminari S, Coiffier B, et al. Clinicopathologic characteristics

lymphoma: Analysis of the international peripheral T-cell lymphoma project. Journal of Clinical Oncology.

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[15] Au WY, Pang A, Choy C, Chim CS, Kwong YL. Quantification of circulating

of angioimmunoblastic T-cell

[11] Liu HL, Hoppe RT, Kohler S, Harvell JD, Reddy S, Kim YH. CD30+ cutaneous lymphoproliferative disorders: The Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Journal of the American Academy of Dermatology.

[2] Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood.

[3] Matutes E. The 2017 WHO update on mature T- and natural killer (NK) cell neoplasms. International Journal of Laboratory Hematology. 2018;**40**

[4] Tang T, Tay K, Quek R, Tao M, Tan SY, Tan L, et al. Peripheral T-cell lymphoma: Review and updates of current management strategies. Advances in Hematology.

[5] Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical

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[6] Au WY, Ma SY, Chim CS, Choy C, Loong F, Lie AK, et al. Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: A single center experience of 10 years. Annals of Oncology. 2005;**16**(2):206-214

[7] Lim ST, Hee SW, Quek R, Lim LC, Yap SP, Loong EL, et al. Comparative analysis of extra-nodal NK/T-cell lymphoma and peripheral T-cell lymphoma: Significant differences in clinical characteristics and prognosis. European Journal of Haematology.

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[29] Corradini P, Tarella C, Zallio F, Dodero A, Zanni M, Valagussa P, et al. Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia. 2006;**20**(9):1533-1538

[30] Reimer P, Rudiger T, Geissinger E, Weissinger F, Nerl C, Schmitz N, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: Results of a prospective multicenter study. Journal of Clinical Oncology. 2009;**27**(1):106-113

[31] d'Amore F, Relander T, Lauritzsen GF, Jantunen E, Hagberg H, Anderson H, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. Journal of Clinical Oncology. 2012;**30**(25):3093-3099

[32] Yam C, Landsburg DJ, Lin X, Mato A, Svoboda J, Loren A, et al. Autologous stem cell transplantation in first complete remission may not extend progression free survival in patients with ALK-negative peripheral T cell lymphoma. Blood. 2015;**126**(23):3183

[33] Tang T, Khoo LP, Lim C, Ham JS, Kim SJ, Hong H, et al. Outcomes of patients with peripheral T-cell lymphoma in first complete remission: Data from three tertiary Asian cancer centers. Blood Cancer Journal. 2017;**7**(12):653

[34] Fossard G, Broussais F, Coelho I, Bailly S, Nicolas-Virelizier E, Toussaint E, et al. Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients in response after induction: An analysis of patients from LYSA centers. Annals of Oncology. 2018;**29**(3):715-723

[35] Corradini P, Vitolo U, Rambaldi A, Miceli R, Patriarca F, Gallamini A, et al. Intensified chemo-immunotherapy with or without stem cell transplantation in newly diagnosed patients with peripheral T-cell lymphoma. Leukemia. 2014;**28**(9):1885-1891

[36] Schmitz N, Nickelsen M, Altmann B, Ziepert M, Bouabdallah K, Gisselbrecht C, et al. Allogeneic or autologous transplantation as first-line therapy for younger patients with peripheral T-cell lymphoma: Results of the interim analysis of the AATT trial. Journal of Clinical Oncology. 2015;**33**(15\_suppl):8507

[37] Smith SM, Burns LJ, Besien K, LeRademacher J, He W, Fenske TS, et al. Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma. Journal of Clinical Oncology. 2013;**31**(25):3100-3109

[38] Schmitz N, Lenz G, Stelljes M. Allogeneic hematopoietic stem cell transplantation for T-cell lymphomas. Blood. 2018;**132**(3):245-253

[39] Sabattini E, Pizzi M, Tabanelli V, Baldin P, Sacchetti CS, Agostinelli C, et al. CD30 expression in peripheral T-cell lymphomas. Haematologica. 2013;**98**(8):e81-e82

[40] Horwitz SM, Advani RH, Bartlett NL, Jacobsen ED, Sharman JP, O'Connor OA, et al. Objective responses in relapsed T-cell lymphomas with singleagent brentuximab vedotin. Blood. 2014;**123**(20):3095-3100

[41] Lamarque M, Bossard C, Contejean A, Brice P, Parrens M, Le Gouill S, et al. Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: The French named patient program experience in 56 patients. Haematologica. 2016;**101**(3):e103-e106

[42] Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Brentuximab

**19**

*Overview of T-cell Lymphomas*

2017;**390**(10094):555-566

2018;**9**(15):11887-11888

2013;**19**(24):6657-6661

O'Connor OA. Pralatrexate pharmacology and clinical

*DOI: http://dx.doi.org/10.5772/intechopen.85058*

[49] Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood.

[50] Sawas A, Radeski D, O'Connor OA. Belinostat in patients with refractory

2011;**117**(22):5827-5834

2015;**6**(4):202-208

or relapsed peripheral T-cell lymphoma: A perspective review. Therapeutic Advances in Hematology.

anaplastic large-cell lymphoma: Results of a phase II study. Journal of Clinical Oncology. 2012;**30**(18):2190-2196

[43] Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): An international, open-label, randomised, phase 3, multicentre trial. Lancet (London, England).

[44] Prince HM, Gautam A, Kim YH. Brentuximab vedotin: Targeting CD30 as standard in CTCL. Oncotarget.

[45] Marchi E, Mangone M, Zullo K,

development. Clinical Cancer Research.

[46] O'Connor OA, Horwitz S, Hamlin P, Portlock C, Moskowitz CH, Sarasohn D, et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. Journal of Clinical Oncology. 2009;**27**(26):4357-4364

[47] O'Connor OA, Pro B, Pinter-Brown L,

[48] Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. Journal of Clinical Oncology. 2012;**30**(6):631-636

Bartlett N, Popplewell L, Coiffier B, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: Results from the pivotal PROPEL study. Journal of Clinical Oncology.

2011;**29**(9):1182-1189

vedotin (SGN-35) in patients with relapsed or refractory systemic

*Overview of T-cell Lymphomas DOI: http://dx.doi.org/10.5772/intechopen.85058*

*Peripheral T-cell Lymphomas*

2006;**20**(9):1533-1538

[31] d'Amore F, Relander T, Lauritzsen GF, Jantunen E,

2012;**30**(25):3093-3099

[32] Yam C, Landsburg DJ, Lin X, Mato A, Svoboda J, Loren A, et al. Autologous stem cell transplantation in first complete remission may not extend progression free survival in patients with ALK-negative peripheral T cell lymphoma. Blood. 2015;**126**(23):3183

[33] Tang T, Khoo LP, Lim C, Ham JS, Kim SJ, Hong H, et al. Outcomes of patients with peripheral T-cell lymphoma in first complete remission: Data from three tertiary Asian cancer centers. Blood Cancer

Journal. 2017;**7**(12):653

2018;**29**(3):715-723

[34] Fossard G, Broussais F,

Coelho I, Bailly S, Nicolas-Virelizier E, Toussaint E, et al. Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients in response after induction: An analysis of patients from LYSA centers. Annals of Oncology.

of peripheral T-cell lymphoma. Blood Advances. 2017;**1**(24):2138-2146

[35] Corradini P, Vitolo U, Rambaldi A, Miceli R, Patriarca F, Gallamini A, et al. Intensified chemo-immunotherapy with or without stem cell transplantation in newly diagnosed patients with peripheral T-cell lymphoma. Leukemia.

Altmann B, Ziepert M, Bouabdallah K, Gisselbrecht C, et al. Allogeneic or autologous transplantation as first-line therapy for younger patients with peripheral T-cell lymphoma: Results of the interim analysis of the AATT trial. Journal of Clinical Oncology.

2014;**28**(9):1885-1891

2015;**33**(15\_suppl):8507

[37] Smith SM, Burns LJ, Besien K, LeRademacher J, He W, Fenske TS, et al. Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma. Journal of Clinical Oncology. 2013;**31**(25):3100-3109

[38] Schmitz N, Lenz G, Stelljes M. Allogeneic hematopoietic stem cell transplantation for T-cell lymphomas.

[39] Sabattini E, Pizzi M, Tabanelli V, Baldin P, Sacchetti CS, Agostinelli C, et al. CD30 expression in peripheral T-cell lymphomas. Haematologica.

[40] Horwitz SM, Advani RH, Bartlett NL, Jacobsen ED, Sharman JP, O'Connor OA, et al. Objective responses in relapsed T-cell lymphomas with singleagent brentuximab vedotin. Blood.

[42] Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Brentuximab

Blood. 2018;**132**(3):245-253

2013;**98**(8):e81-e82

2014;**123**(20):3095-3100

[41] Lamarque M, Bossard C, Contejean A, Brice P, Parrens M, Le Gouill S, et al. Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: The French named patient program experience in 56 patients. Haematologica. 2016;**101**(3):e103-e106

[36] Schmitz N, Nickelsen M,

[29] Corradini P, Tarella C, Zallio F, Dodero A, Zanni M, Valagussa P, et al. Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia.

[30] Reimer P, Rudiger T, Geissinger E, Weissinger F, Nerl C, Schmitz N, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: Results of a prospective multicenter study. Journal of Clinical Oncology. 2009;**27**(1):106-113

Hagberg H, Anderson H, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. Journal of Clinical Oncology.

**18**

vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: Results of a phase II study. Journal of Clinical Oncology. 2012;**30**(18):2190-2196

[43] Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): An international, open-label, randomised, phase 3, multicentre trial. Lancet (London, England). 2017;**390**(10094):555-566

[44] Prince HM, Gautam A, Kim YH. Brentuximab vedotin: Targeting CD30 as standard in CTCL. Oncotarget. 2018;**9**(15):11887-11888

[45] Marchi E, Mangone M, Zullo K, O'Connor OA. Pralatrexate pharmacology and clinical development. Clinical Cancer Research. 2013;**19**(24):6657-6661

[46] O'Connor OA, Horwitz S, Hamlin P, Portlock C, Moskowitz CH, Sarasohn D, et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. Journal of Clinical Oncology. 2009;**27**(26):4357-4364

[47] O'Connor OA, Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: Results from the pivotal PROPEL study. Journal of Clinical Oncology. 2011;**29**(9):1182-1189

[48] Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. Journal of Clinical Oncology. 2012;**30**(6):631-636

[49] Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;**117**(22):5827-5834

[50] Sawas A, Radeski D, O'Connor OA. Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: A perspective review. Therapeutic Advances in Hematology. 2015;**6**(4):202-208

**21**

malignancies.

**Chapter 3**

**Abstract**

**1. Introduction**

*Suzanne D. Turner*

Anaplastic Large Cell Lymphoma

Anaplastic large cell lymphoma (ALCL) describes a distinct group of T cell lymphomas characterised by cell surface expression of CD30. At least three entities of ALCL exist, with similar cellular morphology but varying clinical courses and pathology: systemic ALCL, anaplastic lymphoma kinase (ALK)-positive, systemic ALCL ALK− and primary cutaneous ALCL. A fourth provisional entity associated with breast implants has been proposed, named breast implant-associated (BIA)- ALCL. ALCL have varying clinical outcomes, affect both children and adults, and range from being well-characterised at the genetic level to relatively unknown, predominantly due to the relative rarity of this group of malignancies. Current therapeutic approaches include standard chemotherapeutic agents as well as novel

drugs including monoclonal antibodies and kinase inhibitors.

**Keywords:** anaplastic large cell lymphoma, anaplastic lymphoma kinase, tyrosine kinase inhibitors, peripheral T cell lymphoma, BIA-ALCL

Anaplastic large cell lymphoma (ALCL) was first described in 1985 as a CD30 positive (or ki-1+) histiocytic lymphoma, later re-classified as a distinct clinical entity, ALCL [1]. The presence of a chromosomal translocation in this malignancy was described independently by several authors in 1989–1990 [2–5]. This was further refined in 1994 on cloning of the t(2;5)(p23;q35) translocation breakpoint product, identified as a fusion protein of Nucleophosmin 1 (NPM) and anaplastic lymphoma kinase (ALK), the latter a previously uncharacterized protein named after the disease from which it was cloned [6]. Sometime later in 2008, systemic (s) ALCL was divided into two provisional entities: ALCL, ALK+ and ALCL, ALK− which were confirmed as distinct entities in the revised 4th edition of the WHO classification of tumours of haemopoietic and lymphoid tissues [7]. The revised 4th edition also includes a new provisional entity of ALCL associated with breast implants, breast implant-associated (BIA)-ALCL which may consist of at least two clinically distinguishable forms, if not a spectrum of disease, ranging from sub-capsular seroma fluid to aggressive, infiltrating masses with good and poor prognoses respectively [8, 9]. As well as systemic forms of the disease, there exists a cutaneous type belonging to the class of primary cutaneous CD30-positive T cell lymphoproliferative disorders—primary cutaneous (pc) ALCL [7]. In this chapter, the clinical and pathological presentations of each of these disease entities will be presented and discussed as will the biology underlying these

## **Chapter 3**

## Anaplastic Large Cell Lymphoma

*Suzanne D. Turner*

## **Abstract**

Anaplastic large cell lymphoma (ALCL) describes a distinct group of T cell lymphomas characterised by cell surface expression of CD30. At least three entities of ALCL exist, with similar cellular morphology but varying clinical courses and pathology: systemic ALCL, anaplastic lymphoma kinase (ALK)-positive, systemic ALCL ALK− and primary cutaneous ALCL. A fourth provisional entity associated with breast implants has been proposed, named breast implant-associated (BIA)- ALCL. ALCL have varying clinical outcomes, affect both children and adults, and range from being well-characterised at the genetic level to relatively unknown, predominantly due to the relative rarity of this group of malignancies. Current therapeutic approaches include standard chemotherapeutic agents as well as novel drugs including monoclonal antibodies and kinase inhibitors.

**Keywords:** anaplastic large cell lymphoma, anaplastic lymphoma kinase, tyrosine kinase inhibitors, peripheral T cell lymphoma, BIA-ALCL

## **1. Introduction**

Anaplastic large cell lymphoma (ALCL) was first described in 1985 as a CD30 positive (or ki-1+) histiocytic lymphoma, later re-classified as a distinct clinical entity, ALCL [1]. The presence of a chromosomal translocation in this malignancy was described independently by several authors in 1989–1990 [2–5]. This was further refined in 1994 on cloning of the t(2;5)(p23;q35) translocation breakpoint product, identified as a fusion protein of Nucleophosmin 1 (NPM) and anaplastic lymphoma kinase (ALK), the latter a previously uncharacterized protein named after the disease from which it was cloned [6]. Sometime later in 2008, systemic (s) ALCL was divided into two provisional entities: ALCL, ALK+ and ALCL, ALK− which were confirmed as distinct entities in the revised 4th edition of the WHO classification of tumours of haemopoietic and lymphoid tissues [7]. The revised 4th edition also includes a new provisional entity of ALCL associated with breast implants, breast implant-associated (BIA)-ALCL which may consist of at least two clinically distinguishable forms, if not a spectrum of disease, ranging from sub-capsular seroma fluid to aggressive, infiltrating masses with good and poor prognoses respectively [8, 9]. As well as systemic forms of the disease, there exists a cutaneous type belonging to the class of primary cutaneous CD30-positive T cell lymphoproliferative disorders—primary cutaneous (pc) ALCL [7]. In this chapter, the clinical and pathological presentations of each of these disease entities will be presented and discussed as will the biology underlying these malignancies.

## **2. Systemic ALCL**

## **2.1 Clinical course**

The large majority of ALCL, ALK+ are diagnosed in a younger patient population with a median age of 10.2–11 and have a relatively good prognosis (>80% overall survival; OS) [10–15]. In contrast ALCL, ALK− more often affects an older demographic (40–65 years of age) and has a poor prognosis (<50% OS) [16–19]. Whether these different clinical outcomes are age-related or due to inherent properties of the malignancies remains to be determined although in support of the latter, ALK− ALCL carrying DUSP22 rearrangements have been reported to have a superior 5-year OS of 90% (compared to 17% for TP63 rearranged cases and 42% for ALK−/DUSP22−/ TP63− cases) although if patients are stratified according to age rather than ALK status, the outcome in response to treatment is the same [17, 19, 20]. The relatively high survival rates of patients diagnosed with ALCL, ALK+ may also be attributable to the host immune response whereby cytotoxic T lymphocytes, helper T cells and B cells responding to ALK have been detected in patients [21, 22]. Patients with ALCL, ALK+ mount an immune response to the ALK protein in the form of a humoral antibody response [23]. In fact, the titre of ALK autoantibodies in a patient's serum can be predictive of outcome with an inverse correlation between ALK antibodies and relapse [24]. This prognostic factor can be extended further when combined with the presence or absence of minimal disseminated disease (MDD), with children having low ALK autoantibody titres combined with presence of MDD being of high risk, with the converse indicative of low risk [25].

### **2.2 Histopathological presentation and immunophenotype**

ALCL spans a broad morphological spectrum with sub-types including common (65%), small cell and lymphohistiocytic variants (32% combined) with the latter constituting a poor prognostic variable [26–28]. The unifying feature of ALCL is the presence of CD30 expression on the surface of the tumour cells, particularly the larger ones. CD30 is a marker of activated immune cells but does not distinguish between a T or B cell origin when applied in isolation. Hence, for a diagnosis of a T cell lymphoma, a cell surface protein, or combination of proteins unique to T cells must be detected. In this regard, many ALCL express CD4, CD2 and/or CD5 but often lack CD3. The positive expression of CD4 in the absence of CD8 combined with the presence of cytotoxic proteins such as TIA-1, Granzyme B and/or perforin is at odds with the presumed cytotoxic T cell origin of ALCL [7, 29]. However, in some cases, no T cell specific proteins are detectable and these are categorised as being 'null cell', although the majority demonstrate molecular rearrangements of the T cell receptor (TCR) [30].

## **2.3 Underlying genetic alterations**

## *2.3.1 ALCL, ALK+*

ALCL is, in general, a genetically stable cancer with few common defining genetic alterations besides translocations involving ALK [31, 32]. In this regard, the t(2;5) (p23;q35) generating NPM-ALK at the breakpoint is the most common event with many variants having been published over the years (**Table 1**) [33]. The common expression of NPM-ALK, and its nuclear and cytoplasmic location as opposed to cytoplasmic-alone position as seen with many of the other variants, may account for its predominance in ALCL, ALK+; nuclear location may provide a competitive advantage over cytoplasmic alone. Alternatively, the *NPM1* gene on chromosome 5 may be

**23**

**Figure 1.**

*Anaplastic Large Cell Lymphoma*

**Chromosomal alteration**

**Table 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.81382*

t(2;3)(p23;q12.2) TFG-ALK (short, long and

*Overview of ALK fusion partners identified in ALCL, ALK+.*

more prone to breakage and fusion with new partners due to its active transcription at the same time as *ALK*, although there is no evidence to suggest this is the case. What is clear, is that all reported ALK fusion proteins generate a hyperactive tyrosine kinase that is ligand-independent, driving cellular proliferation and survival [33]. Taking the example of NPM-ALK, this fusion protein retains the oligomerisation domains of NPM1 and the entire intracellular portion of ALK encoding the kinase domain, resulting in dimerization, auto-phosphorylation and subsequent hyperactivity initiat-

*NPM-ALK activates a plethora of signalling pathways conferring many of the cancer hallmarks on tumour cells. NPM-ALK autophosphorylates tyrosine residues providing docking sites for SH2 domain-containing proteins and the development of a signalosome consisting of at least 46 proteins [35]. Key pathways involved in cell survival and proliferation include the PI 3-Kinase/Akt, Ras/MAP Kinase and JAK/STAT pathways as well as PLCγ [36–41]. While activation of JNK and PI 3-Kinase by NPM-ALK can drive cell proliferation, they also inactivate p53 by ubiquitin-mediated degradation [42]. NPM-ALK also activates immunomodulatory pathways including up-regulation of PDL1 mediated by STAT3, as well as silencing some proteins by epigenetic means (green arrow,* **Figure 1***), including those associated with signalling downstream of a functional TCR [43–47]. In addition, NPM-ALK directs metabolic activity of the cells shifting to aerobic glycolysis with* 

*increased lactate and biomass production promoting cell survival [48].*

t(2;5)(p23;q35) NPM-ALK Nucleus and cytoplasm [2–6]

t(1;2)(q25;p23) TPM3-ALK Cytoplasm [136] Inv(2)(p23;q35) ATIC-ALK Cytoplasm [137, 138] t(X;2)(q11–12;p23) MSN-ALK Membrane [139] t(2;17)(p23;q23) CLTC-ALK Cytoplasm (granular) [140, 141] t(2;22)(p23;q11.2) MYH9-ALK Cytoplasm [142] t(2;19)(p23;q13.1) TPM4-ALK Cytoplasm [143] t(2;17)(p23;q25) RNF213/ALO17-ALK Cytoplasm [144]

extra-long isoforms)

**Fusion protein Cellular location References**

Cytoplasm [134, 135]

ing a whole plethora of signal transduction pathways (**Figure 1**) [6, 34].

#### *Anaplastic Large Cell Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.81382*


#### **Table 1.**

*Peripheral T-cell Lymphomas*

with the converse indicative of low risk [25].

**2.3 Underlying genetic alterations**

*2.3.1 ALCL, ALK+*

**2.2 Histopathological presentation and immunophenotype**

ALCL spans a broad morphological spectrum with sub-types including common (65%), small cell and lymphohistiocytic variants (32% combined) with the latter constituting a poor prognostic variable [26–28]. The unifying feature of ALCL is the presence of CD30 expression on the surface of the tumour cells, particularly the larger ones. CD30 is a marker of activated immune cells but does not distinguish between a T or B cell origin when applied in isolation. Hence, for a diagnosis of a T cell lymphoma, a cell surface protein, or combination of proteins unique to T cells must be detected. In this regard, many ALCL express CD4, CD2 and/or CD5 but often lack CD3. The positive expression of CD4 in the absence of CD8 combined with the presence of cytotoxic proteins such as TIA-1, Granzyme B and/or perforin is at odds with the presumed cytotoxic T cell origin of ALCL [7, 29]. However, in some cases, no T cell specific proteins are detectable and these are categorised as being 'null cell', although the majority demonstrate molecular rearrangements of the T cell receptor (TCR) [30].

ALCL is, in general, a genetically stable cancer with few common defining genetic alterations besides translocations involving ALK [31, 32]. In this regard, the t(2;5) (p23;q35) generating NPM-ALK at the breakpoint is the most common event with many variants having been published over the years (**Table 1**) [33]. The common expression of NPM-ALK, and its nuclear and cytoplasmic location as opposed to cytoplasmic-alone position as seen with many of the other variants, may account for its predominance in ALCL, ALK+; nuclear location may provide a competitive advantage over cytoplasmic alone. Alternatively, the *NPM1* gene on chromosome 5 may be

The large majority of ALCL, ALK+ are diagnosed in a younger patient population

with a median age of 10.2–11 and have a relatively good prognosis (>80% overall survival; OS) [10–15]. In contrast ALCL, ALK− more often affects an older demographic (40–65 years of age) and has a poor prognosis (<50% OS) [16–19]. Whether these different clinical outcomes are age-related or due to inherent properties of the malignancies remains to be determined although in support of the latter, ALK− ALCL carrying DUSP22 rearrangements have been reported to have a superior 5-year OS of 90% (compared to 17% for TP63 rearranged cases and 42% for ALK−/DUSP22−/ TP63− cases) although if patients are stratified according to age rather than ALK status, the outcome in response to treatment is the same [17, 19, 20]. The relatively high survival rates of patients diagnosed with ALCL, ALK+ may also be attributable to the host immune response whereby cytotoxic T lymphocytes, helper T cells and B cells responding to ALK have been detected in patients [21, 22]. Patients with ALCL, ALK+ mount an immune response to the ALK protein in the form of a humoral antibody response [23]. In fact, the titre of ALK autoantibodies in a patient's serum can be predictive of outcome with an inverse correlation between ALK antibodies and relapse [24]. This prognostic factor can be extended further when combined with the presence or absence of minimal disseminated disease (MDD), with children having low ALK autoantibody titres combined with presence of MDD being of high risk,

**2. Systemic ALCL**

**2.1 Clinical course**

**22**

*Overview of ALK fusion partners identified in ALCL, ALK+.*

more prone to breakage and fusion with new partners due to its active transcription at the same time as *ALK*, although there is no evidence to suggest this is the case. What is clear, is that all reported ALK fusion proteins generate a hyperactive tyrosine kinase that is ligand-independent, driving cellular proliferation and survival [33]. Taking the example of NPM-ALK, this fusion protein retains the oligomerisation domains of NPM1 and the entire intracellular portion of ALK encoding the kinase domain, resulting in dimerization, auto-phosphorylation and subsequent hyperactivity initiating a whole plethora of signal transduction pathways (**Figure 1**) [6, 34].

#### **Figure 1.**

*NPM-ALK activates a plethora of signalling pathways conferring many of the cancer hallmarks on tumour cells. NPM-ALK autophosphorylates tyrosine residues providing docking sites for SH2 domain-containing proteins and the development of a signalosome consisting of at least 46 proteins [35]. Key pathways involved in cell survival and proliferation include the PI 3-Kinase/Akt, Ras/MAP Kinase and JAK/STAT pathways as well as PLCγ [36–41]. While activation of JNK and PI 3-Kinase by NPM-ALK can drive cell proliferation, they also inactivate p53 by ubiquitin-mediated degradation [42]. NPM-ALK also activates immunomodulatory pathways including up-regulation of PDL1 mediated by STAT3, as well as silencing some proteins by epigenetic means (green arrow,* **Figure 1***), including those associated with signalling downstream of a functional TCR [43–47]. In addition, NPM-ALK directs metabolic activity of the cells shifting to aerobic glycolysis with increased lactate and biomass production promoting cell survival [48].*

While ALK translocations are diagnostic of ALCL, ALK+ and are central to disease pathogenesis, the role of other contributing mutations is largely unknown as few consistent genetic abnormalities besides those generating ALK translocations have been reported. This may, in part, be due to the plethora a cancer hallmarks that can be driven by NPM-ALK alone (**Figure 1**). However, array comparative genomic hybridization (aCGH) studies have highlighted some commonalities [31, 32]. For example, gains of chromosomes 7, 6q, 17p, 17q24-qter and losses of chromosomes 4q13-q21, 11q14 and 13q although the significance of these is unknown [32]. However, a higher number of genomic imbalances as detected by aCGH at a resolution of 1 MB, has been associated with a worse prognosis [31].

The recognition of NPM-ALK as a driving oncogenic event and the paucity of other reported consistent genomic/genetic abnormalities in ALCL, ALK+ has led to studies of the epigenetics of ALCL [31, 49, 50]. Profiling of CpG methylation in ALCL defined a number of genes silenced in these malignancies including the TCR signalling-related proteins Zap70, LAT, CD3ε, SLP76 and the IL2Rγ chain [43, 45–47, 49, 51]. Given that NPM-ALK can substitute for signalling normally induced via an engaged TCR, activation of these proximal TCR signalling proteins may be detrimental to cell survival resulting in their evolutionary down-regulation [38, 52]. Furthermore, a number of miRNA have been implicated in tumorigenesis including miR17-92, miR135b, miR29a and miR16 [53–56].

### *2.3.2 ALCL, ALK−*

By their very definition, ALCL, ALK− lack expression of ALK fusion proteins, but until recently, few studies had found major contributory and consistent mutations. DUSP22 rearrangements leading to loss of expression of DUSP22 have been reported in as many as 30% of cases and activating *JAK1/STAT3* mutations in 20% [19, 57, 58]. In addition, rearrangements leading to *TP63* mutation (8% of cases) and ERBB4 truncation have been demonstrated as have novel, rare rearrangements leading to the generation of NcoR2-ROS1, NFkB2-ROS1 and NFkB2-TYK2 fusion proteins [19, 57, 59, 60]. In addition, similar to ALK+ ALCL, miRNA have been implicated in disease pathogenesis including miR155 as well as others that enable a molecular distinction between ALCL, ALK+ and ALK− as well as peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) [61–64]. Likewise, genomic classifiers of ALCL, ALK− amongst other peripheral T cell lymphomas have been demonstrated using a variety of genomic analysis techniques and includes the differentiating 3-gene signature of *TNFRSF8*, *BATF3* and *TMOD1* [65–68]. SNP arrays have also led to the identification of recurrent losses at 17p13 and/or 6q21 where the *TP53* and *PRDM1* genes are located respectively, in as many as 52% of cases suggestive of a role for the loss of the p53 and BLIMP1 proteins in disease pathogenesis [69].

## **3. BIA-ALCL**

BIA-ALCL is a relatively new addition to the spectrum of ALCL, although the first case was reported in 1997, but did not receive much attention until further cases were identified and published, and the FDA acknowledged an association in 2011 [70, 71]. In March 2015, the French health minister issued a warning following reports of 18 cases in France [72]. A further follow-up report released by the FDA in 2017 described 414 medical device reports and 9 deaths associated with BIA-ALCL [73]. Many case series have been reviewed and reported since, with data from France, Italy,

**25**

*Anaplastic Large Cell Lymphoma*

**3.1 Clinical course**

also been put forward [88–90].

**3.3 Underlying genetic alterations**

elucidate the underlying genetics.

**4. Primary cutaneous ALCL**

also develop pcALCL.

**4.1 Clinical course**

*DOI: http://dx.doi.org/10.5772/intechopen.81382*

The Netherlands, UK, Australia and the USA being prevalent [74–80]. Most recently, seven cases have been reported in Latin America [81]. There are approximately 5–10 million women with breast implants worldwide with rates of BIA-ALCL being proportionately rare although difficult to put an exact figure to. Dependent on the study conducted, incidence rates range from 1 to 89 cases per million women with breast implants [82, 83]. This reaches a much higher incidence if one considers women with textured implants alone. Almost all cases reported to date have been associated with a breast implant of a textured surface at some point during the history of the patient; whilst rare cases have been reported in women with smooth implants, the patient had been in receipt of a textured implant at some stage [78, 84]. In addition, both saline and silicone filled implants have been implicated in patients with BIA-ALCL. The tumour cells generally present as a monoclonal expansion of CD30-positive cells, as

BIA-ALCL appears to represent at least two clinical entities if not a spectrum of malignancies; patients present on most occasions with an indolent seroma with rarer incidences of invasive solid masses [77]. Indeed, cases have been reported of tumour growth into the ribs with metastases to distant lymph nodes [85, 86].

Like sALCL, BIA-ALCL is characterised by CD30 expression on lymphoid cells, in the latter situation contained within the peri-prosthetic effusion [28, 87]. These cells can be detected by immunohistochemistry, cytology and flow cytometry of seroma fluid or any solid mass [85]. A Th17/Th1 origin has been proposed whereby tumour cells secrete IFNγ, IL6, IL8, IL17 and TGFβ although a Th2 derivation has

Like ALCL, ALK−, BIA-ALCL has not to date been associated with genomic events leading to activation of ALK. However, in concert with ALCL, ALK−, activating mutations of JAK/STAT proteins have been reported in a very few cases [91, 92]. Given the relative rarity of this disease, larger scale studies are required to

While skin involvement can occur as an extranodal manifestation of sALCL, isolated cutaneous disease can also occur, although this is largely ALK-negative [17]. Primary cutaneous ALCL belongs to the spectrum of CD30 positive lymphoproliferative disorders (LPDs) and like BIA-ALCL is largely indolent in nature. While largely affecting adults who present with isolated, ulcerating nodules, children can

Like systemic ALCL, ALK−, cutaneous ALCL is also a disease of an older demographic with the majority of patients being over 50 years of age, yet is closer

an effusion within the fibrous capsule surrounding the implant [78].

**3.2 Histopathological presentation and immunophenotype**

#### *Anaplastic Large Cell Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.81382*

The Netherlands, UK, Australia and the USA being prevalent [74–80]. Most recently, seven cases have been reported in Latin America [81]. There are approximately 5–10 million women with breast implants worldwide with rates of BIA-ALCL being proportionately rare although difficult to put an exact figure to. Dependent on the study conducted, incidence rates range from 1 to 89 cases per million women with breast implants [82, 83]. This reaches a much higher incidence if one considers women with textured implants alone. Almost all cases reported to date have been associated with a breast implant of a textured surface at some point during the history of the patient; whilst rare cases have been reported in women with smooth implants, the patient had been in receipt of a textured implant at some stage [78, 84]. In addition, both saline and silicone filled implants have been implicated in patients with BIA-ALCL. The tumour cells generally present as a monoclonal expansion of CD30-positive cells, as an effusion within the fibrous capsule surrounding the implant [78].

## **3.1 Clinical course**

*Peripheral T-cell Lymphomas*

prognosis [31].

*2.3.2 ALCL, ALK−*

While ALK translocations are diagnostic of ALCL, ALK+ and are central to disease pathogenesis, the role of other contributing mutations is largely unknown as few consistent genetic abnormalities besides those generating ALK translocations have been reported. This may, in part, be due to the plethora a cancer hallmarks that can be driven by NPM-ALK alone (**Figure 1**). However, array comparative genomic hybridization (aCGH) studies have highlighted some commonalities [31, 32]. For example, gains of chromosomes 7, 6q, 17p, 17q24-qter and losses of chromosomes 4q13-q21, 11q14 and 13q although the significance of these is unknown [32]. However, a higher number of genomic imbalances as detected by aCGH at a resolution of 1 MB, has been associated with a worse

The recognition of NPM-ALK as a driving oncogenic event and the paucity of other reported consistent genomic/genetic abnormalities in ALCL, ALK+ has led to studies of the epigenetics of ALCL [31, 49, 50]. Profiling of CpG methylation in ALCL defined a number of genes silenced in these malignancies including the TCR

By their very definition, ALCL, ALK− lack expression of ALK fusion proteins, but until recently, few studies had found major contributory and consistent mutations. DUSP22 rearrangements leading to loss of expression of DUSP22 have been reported in as many as 30% of cases and activating *JAK1/STAT3* mutations in 20% [19, 57, 58]. In addition, rearrangements leading to *TP63* mutation (8% of cases) and ERBB4 truncation have been demonstrated as have novel, rare rearrangements leading to the generation of NcoR2-ROS1, NFkB2-ROS1 and NFkB2-TYK2 fusion proteins [19, 57, 59, 60]. In addition, similar to ALK+ ALCL, miRNA have been implicated in disease pathogenesis including miR155 as well as others that enable a molecular distinction between ALCL, ALK+ and ALK− as well as peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) [61–64]. Likewise, genomic classifiers of ALCL, ALK− amongst other peripheral T cell lymphomas have been demonstrated using a variety of genomic analysis techniques and includes the differentiating 3-gene signature of *TNFRSF8*, *BATF3* and *TMOD1* [65–68]. SNP arrays have also led to the identification of recurrent losses at 17p13 and/or 6q21 where the *TP53* and *PRDM1* genes are located respectively, in as many as 52% of cases suggestive of a role for the loss of the p53 and BLIMP1 proteins in disease pathogenesis [69].

BIA-ALCL is a relatively new addition to the spectrum of ALCL, although the first case was reported in 1997, but did not receive much attention until further cases were identified and published, and the FDA acknowledged an association in 2011 [70, 71]. In March 2015, the French health minister issued a warning following reports of 18 cases in France [72]. A further follow-up report released by the FDA in 2017 described 414 medical device reports and 9 deaths associated with BIA-ALCL [73]. Many case series have been reviewed and reported since, with data from France, Italy,

signalling-related proteins Zap70, LAT, CD3ε, SLP76 and the IL2Rγ chain [43, 45–47, 49, 51]. Given that NPM-ALK can substitute for signalling normally induced via an engaged TCR, activation of these proximal TCR signalling proteins may be detrimental to cell survival resulting in their evolutionary down-regulation [38, 52]. Furthermore, a number of miRNA have been implicated in tumorigenesis

including miR17-92, miR135b, miR29a and miR16 [53–56].

**24**

**3. BIA-ALCL**

BIA-ALCL appears to represent at least two clinical entities if not a spectrum of malignancies; patients present on most occasions with an indolent seroma with rarer incidences of invasive solid masses [77]. Indeed, cases have been reported of tumour growth into the ribs with metastases to distant lymph nodes [85, 86].

### **3.2 Histopathological presentation and immunophenotype**

Like sALCL, BIA-ALCL is characterised by CD30 expression on lymphoid cells, in the latter situation contained within the peri-prosthetic effusion [28, 87]. These cells can be detected by immunohistochemistry, cytology and flow cytometry of seroma fluid or any solid mass [85]. A Th17/Th1 origin has been proposed whereby tumour cells secrete IFNγ, IL6, IL8, IL17 and TGFβ although a Th2 derivation has also been put forward [88–90].

### **3.3 Underlying genetic alterations**

Like ALCL, ALK−, BIA-ALCL has not to date been associated with genomic events leading to activation of ALK. However, in concert with ALCL, ALK−, activating mutations of JAK/STAT proteins have been reported in a very few cases [91, 92]. Given the relative rarity of this disease, larger scale studies are required to elucidate the underlying genetics.

## **4. Primary cutaneous ALCL**

While skin involvement can occur as an extranodal manifestation of sALCL, isolated cutaneous disease can also occur, although this is largely ALK-negative [17]. Primary cutaneous ALCL belongs to the spectrum of CD30 positive lymphoproliferative disorders (LPDs) and like BIA-ALCL is largely indolent in nature. While largely affecting adults who present with isolated, ulcerating nodules, children can also develop pcALCL.

### **4.1 Clinical course**

Like systemic ALCL, ALK−, cutaneous ALCL is also a disease of an older demographic with the majority of patients being over 50 years of age, yet is closer to ALCL, ALK+ in its prognosis, reaching a 5-year OS of over 90% [17]. However, relapse is relatively common in this patient group occurring in as many as 30–40% of patients and some rare cases (12–16%) can progress to systemic disease [93–95]. Spontaneous regression has been reported, although in rare cases with partial regressions being more common [96].

#### **4.2 Histopathological presentation and immunophenotype**

Diagnosis can be difficult with other cutaneous T cell lymphomas such as lymphomatoid papulosis (LyP) and transformed mycosis fungoides (MF) providing differential diagnoses [9]. However, like systemic ALCL, CD30 expression is a defining feature of this malignancy as it is for the other CD30-associated LPDs.

#### **4.3 Underlying genetic alterations**

Due to its relative rarity, sometimes-difficult diagnosis and indolent course, studies of the underlying genetics are few. However, limited studies have elucidated some of the genetic events that may be driving this disease process some of which are also common to sALCL. For example, as in sALCL, DUSP22-IRF4 rearrangements have been detected in 20–57% of pcALCL and ALK expression is seen in rare cases [19, 97–101]. In addition, aCGH has identified gains of 7q31 and losses of 6q16-21 as well as 13q34, collectively in 45% of examined patient specimens [102]. As well as similarities to ALCL, ALK-negative with regards to DUSP22 translocations, upregulation of miR155 has also been observed in both pcALCL and sALCL, ALK− [61, 103]. The functional and clinical significance of these genetic events is still subject to investigation.

## **5. Treatment of ALCL**

As for most peripheral T cell lymphomas, standard combination chemotherapy has been the mainstay of treatment for many years, specifically in the case of systemic disease [14]. In contrast, the relatively indolent cutaneous and breast implant-associated forms are primarily treated by surgical removal [86]. However, as this spectrum of diseases crosses age boundaries, there are age-specific differences in therapeutic approaches.

#### **5.1 Treatment of children with ALCL**

As mentioned before, the large majority of patients diagnosed with ALCL, ALK+ are children and young adults. As such, the therapeutic approach is tuned to this patient population with children receiving a combination of chemotherapeutic agents with survival rates in excess of 90% [10, 13, 14]. The ALCL99 trial, the largest trial ever to be conducted for children diagnosed with ALCL (n = 352) applied a therapeutic regimen consisting of a B cell protocol (based on NHL-BFM-B) with randomisation of vinblastine [13]. The success of this trial has led to most centres adopting the ALCL99 treatment protocol. Additionally, the success of the ALCL99 trial and the plethora of biological data produced suggest that patients might be stratified according to ALK autoantibody titre and the presence of MDD as discussed above. Indeed, vinblastine monotherapy might be more appropriate for low risk patients reducing both acute and chronic side-effects of the combination chemotherapy protocol [104, 105].

**27**

*Anaplastic Large Cell Lymphoma*

therapy [108, 109].

280 mg/m2

window of therapy [113].

*DOI: http://dx.doi.org/10.5772/intechopen.81382*

**5.3 New and novel treatment options for ALCL**

Adults with ALCL tend to be ALK− and are treated with the standard T cell lymphoma regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) although CHOEP (CHOP + etoposide) has been demonstrated to be superior in the treatment of adult ALCL, ALK+ patients [106]. In the case of BIA-ALCL, surgical excision with complete capsulectomy is recommended and is often sufficient to induce remission particularly for patients that present with a contained seroma [85, 86]. However, patients with aggressive BIA-ALCL that has metastasised require radiotherapy if not chemotherapy, and anecdotal evidence suggests that upfront use of brentuximab vedotin (BV) may benefit these patients [107]. In the case of pcALCL, localised excision and/or radiotherapy is largely prescribed due to the obvious skin presentation, although cases with multi-focal lesions may require more aggressive treatment involving chemo-

In the post-genomic era, targeted agents have become the mainstay of chemotherapy, largely in addition to standard cytotoxic drugs. In the case of ALCL, ALK+, inhibitors of ALK are the obvious choice and many have been developed since the discovery of ALK expression in Non-Small Cell Lung Cancer [14]. The first ALK inhibitor to be developed was Pfizer's PF-2341066, now known as crizotinib, a dual ALK/cMet inhibitor with efficacy in experimental models of ALCL, ALK+ [110]. However, these drugs have been slow to make their way into the clinic for the treatment of ALCL, largely due to its relative rarity and paediatric presentation. A phase I study of crizotinib for children with relapsed/refractory ALK+ malignancies including ALCL, reported seven out of nine patients to achieve a complete response (CR) [111]. A phase II expansion cohort showed overall response rates of 83 and 90% respectively for those children receiving crizotinib at dosages of 165 and

respectively [112]. However, discontinuation of therapy has led to rapid

relapse of both children and adults with ALCL, ALK+ questioning the required

Naturally, ALK inhibitors only apply to the therapy of ALCL, ALK+. In contrast, the common expression of CD30 on all ALCL sub-types means that targeted agents to this cell surface protein should be broadly applicable [114]. In this vein, BV, an anti-CD30 antibody tethered to the microtubule inhibitor monomethyl auristatin E, has shown promising results in clinical trials, although relapse is again an issue with down-regulation of CD30 expression seen [115–117]. However, results of the Phase 3 ALCANZA trial for pcALCL and MF showed impressive results with an objective response rate of 67% in the BV arm (versus 20% in the standard treatment arm: methotrexate or bexarotene) [118]. However, BV is not without its side-effects with peripheral neuropathy being prominent (affecting 67% of patients in the afore-mentioned trial) [118]. Likewise, results of a Phase 2 trial of relapsed/refractory sALCL showed peripheral neuropathy to be a considerable side-effect in 91% of patients although a 5-year OS of 79% was achieved (69% CR, 80% ORR for ALK+ patients and 52% CR, 81% ORR for ALK−) [119]. A randomised Phase 3 trial to establish the efficacy of BV in combination with cyclophosphamide, doxorubicin and prednisolone, in comparison to these chemotherapeutic agents given with vincristine in place of BV, is ongoing for the frontline treatment of CD30-positive lymphomas including ALCL (ECHELON 2; NCT01777152). Other potential therapeutic targets for the treatment of ALCL include PDGFR, JAK/STAT, PD-1/PDL1 and reactivation of p53 [42, 44, 120, 121].

**5.2 Treatment of adults with ALCL**

## **5.2 Treatment of adults with ALCL**

*Peripheral T-cell Lymphomas*

LPDs.

regressions being more common [96].

**4.3 Underlying genetic alterations**

still subject to investigation.

**5. Treatment of ALCL**

ences in therapeutic approaches.

**5.1 Treatment of children with ALCL**

chemotherapy protocol [104, 105].

**4.2 Histopathological presentation and immunophenotype**

to ALCL, ALK+ in its prognosis, reaching a 5-year OS of over 90% [17]. However, relapse is relatively common in this patient group occurring in as many as 30–40% of patients and some rare cases (12–16%) can progress to systemic disease [93–95]. Spontaneous regression has been reported, although in rare cases with partial

Diagnosis can be difficult with other cutaneous T cell lymphomas such as lymphomatoid papulosis (LyP) and transformed mycosis fungoides (MF) providing differential diagnoses [9]. However, like systemic ALCL, CD30 expression is a defining feature of this malignancy as it is for the other CD30-associated

Due to its relative rarity, sometimes-difficult diagnosis and indolent course, studies of the underlying genetics are few. However, limited studies have elucidated some of the genetic events that may be driving this disease process some of which are also common to sALCL. For example, as in sALCL, DUSP22-IRF4 rearrangements have been detected in 20–57% of pcALCL and ALK expression is seen in rare cases [19, 97–101]. In addition, aCGH has identified gains of 7q31 and losses of 6q16-21 as well as 13q34, collectively in 45% of examined patient specimens [102]. As well as similarities to ALCL, ALK-negative with regards to DUSP22 translocations, upregulation of miR155 has also been observed in both pcALCL and sALCL, ALK− [61, 103]. The functional and clinical significance of these genetic events is

As for most peripheral T cell lymphomas, standard combination chemotherapy

has been the mainstay of treatment for many years, specifically in the case of systemic disease [14]. In contrast, the relatively indolent cutaneous and breast implant-associated forms are primarily treated by surgical removal [86]. However, as this spectrum of diseases crosses age boundaries, there are age-specific differ-

As mentioned before, the large majority of patients diagnosed with ALCL, ALK+ are children and young adults. As such, the therapeutic approach is tuned to this patient population with children receiving a combination of chemotherapeutic agents with survival rates in excess of 90% [10, 13, 14]. The ALCL99 trial, the largest trial ever to be conducted for children diagnosed with ALCL (n = 352) applied a therapeutic regimen consisting of a B cell protocol (based on NHL-BFM-B) with randomisation of vinblastine [13]. The success of this trial has led to most centres adopting the ALCL99 treatment protocol. Additionally, the success of the ALCL99 trial and the plethora of biological data produced suggest that patients might be stratified according to ALK autoantibody titre and the presence of MDD as discussed above. Indeed, vinblastine monotherapy might be more appropriate for low risk patients reducing both acute and chronic side-effects of the combination

**26**

Adults with ALCL tend to be ALK− and are treated with the standard T cell lymphoma regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) although CHOEP (CHOP + etoposide) has been demonstrated to be superior in the treatment of adult ALCL, ALK+ patients [106]. In the case of BIA-ALCL, surgical excision with complete capsulectomy is recommended and is often sufficient to induce remission particularly for patients that present with a contained seroma [85, 86]. However, patients with aggressive BIA-ALCL that has metastasised require radiotherapy if not chemotherapy, and anecdotal evidence suggests that upfront use of brentuximab vedotin (BV) may benefit these patients [107]. In the case of pcALCL, localised excision and/or radiotherapy is largely prescribed due to the obvious skin presentation, although cases with multi-focal lesions may require more aggressive treatment involving chemotherapy [108, 109].

### **5.3 New and novel treatment options for ALCL**

In the post-genomic era, targeted agents have become the mainstay of chemotherapy, largely in addition to standard cytotoxic drugs. In the case of ALCL, ALK+, inhibitors of ALK are the obvious choice and many have been developed since the discovery of ALK expression in Non-Small Cell Lung Cancer [14]. The first ALK inhibitor to be developed was Pfizer's PF-2341066, now known as crizotinib, a dual ALK/cMet inhibitor with efficacy in experimental models of ALCL, ALK+ [110]. However, these drugs have been slow to make their way into the clinic for the treatment of ALCL, largely due to its relative rarity and paediatric presentation. A phase I study of crizotinib for children with relapsed/refractory ALK+ malignancies including ALCL, reported seven out of nine patients to achieve a complete response (CR) [111]. A phase II expansion cohort showed overall response rates of 83 and 90% respectively for those children receiving crizotinib at dosages of 165 and 280 mg/m2 respectively [112]. However, discontinuation of therapy has led to rapid relapse of both children and adults with ALCL, ALK+ questioning the required window of therapy [113].

Naturally, ALK inhibitors only apply to the therapy of ALCL, ALK+. In contrast, the common expression of CD30 on all ALCL sub-types means that targeted agents to this cell surface protein should be broadly applicable [114]. In this vein, BV, an anti-CD30 antibody tethered to the microtubule inhibitor monomethyl auristatin E, has shown promising results in clinical trials, although relapse is again an issue with down-regulation of CD30 expression seen [115–117]. However, results of the Phase 3 ALCANZA trial for pcALCL and MF showed impressive results with an objective response rate of 67% in the BV arm (versus 20% in the standard treatment arm: methotrexate or bexarotene) [118]. However, BV is not without its side-effects with peripheral neuropathy being prominent (affecting 67% of patients in the afore-mentioned trial) [118]. Likewise, results of a Phase 2 trial of relapsed/refractory sALCL showed peripheral neuropathy to be a considerable side-effect in 91% of patients although a 5-year OS of 79% was achieved (69% CR, 80% ORR for ALK+ patients and 52% CR, 81% ORR for ALK−) [119]. A randomised Phase 3 trial to establish the efficacy of BV in combination with cyclophosphamide, doxorubicin and prednisolone, in comparison to these chemotherapeutic agents given with vincristine in place of BV, is ongoing for the frontline treatment of CD30-positive lymphomas including ALCL (ECHELON 2; NCT01777152). Other potential therapeutic targets for the treatment of ALCL include PDGFR, JAK/STAT, PD-1/PDL1 and reactivation of p53 [42, 44, 120, 121].

#### *Peripheral T-cell Lymphomas*

Indeed, biological studies have identified a number of potential therapeutic targets, which in some cases, and with time, have been matched to available drugs. However, with relatively few patients, coupled with a good prognosis, at least for children with ALK+ systemic disease, it is difficult to formulate trials to test these agents.

A further approach given the immune response to ALK in patients with ALKpositive disease, is a vaccination strategy [122]. This is especially relevant as ALK expression seems to be limited to tissues of neonatal origin suggesting that sideeffects will be limited [123].

## **6. The origins and pathogenesis of ALCL: a common origin with distinct pathogenesis or different origins converging on a shared histopathology?**

#### **6.1 Cell of origin**

Systemic ALCL presents in the periphery suggestive of a peripheral T cell origin, although as many as 50% of children show mediastinal involvement [29]. In this latter vein, a thymic origin has been proposed whereby gene expression signatures associated with early thymic progenitors (ETP) are detected in ALCL cancer stem cells, in fitting with the detection of transcripts for the t(2;5)(p23;q35) translocation breakpoint product in 2% of cord blood specimens from healthy babies [124, 125]. In addition, studies of epigenetic signatures are in keeping with an ETP origin [49]. As such, it is not inconceivable that ALCL, ALK+ has a thymic, perhaps *in utero* origin in-line with the pathogenesis of paediatric leukaemias [29]. Additionally, this is in keeping with a paediatric presentation and the early-life involution of the thymus. Furthermore, studies of murine models show that events in the periphery once incipient tumour cells emerge from the thymus contribute to disease pathogenesis as discussed below [30].

While ALCL, ALK+ is proposed to emerge from the thymus, a similar origin likely does not apply to ALK-negative disease, including pcALCL, BIA-ALCL and ALCL, ALK−. In these latter cases, circulating peripheral T cells are most probably the cells of origin given the older age of diagnosis and peripheral location, particularly with regards to BIA-ALCL and pcALCL. If this is the case, if the type of T cell that becomes transformed can be identified, this may give clues as to disease pathogenesis. While histopathology indicating an activated CD30-expressing T cell producing cytotoxic proteins, yet also often retaining CD4 expression, has given rise to a presumed cytotoxic T cell origin, recent data challenges this perception [29, 126]. Specifically, analysis of gene expression data suggests a Th17 origin, a T cell that usually responds to large extracellular infectious agents such as bacteria and is often implicated in autoimmune disease [89, 127]. However, given that ALCL often lack expression of TCR-related signalling proteins as well as a functional cell surface TCR, analogies to innate lymphoid cells (ILC), specifically ILC type 3 cells are also apparent [127]. Naturally, the eventual cell phenotype is not necessarily reflective of the cell of origin with environmental events likely contributing to the final observed identity. In this regard, whether in ALCL, ALK+ this is shaped by ALKmediated activities (or is the consequence of other induced (epi)genetic events) remains to be fully elucidated as it does for other ALCL sub-types. In evidence, it has been shown that NPM-ALK induces expression of cytotoxic proteins suggesting that their presence reflects the activities of this inherent transforming event rather than a property of the cell of origin, at least for ALCL, ALK+ [128]. This would

**29**

**Figure 2.**

*cellular transformation.*

*Anaplastic Large Cell Lymphoma*

discounted [88–90].

**6.2 An infectious aetiology?**

*DOI: http://dx.doi.org/10.5772/intechopen.81382*

type may no longer reflect the cell of origin.

partly explain the 'confused' T cell phenotype with both helper and cytotoxic T cell properties apparent. Indeed, plasticity amongst helper T cell subsets is immense and is dependent on the relative expression levels of key transcription factors such as T-bet, RORγ, GATA-3 and Foxp3 as well as cytokines in the microenvironment [129]. Hence, for a T cell aberrantly expressing a variety of genetic changes, embedded in specific inflammatory microenvironments, the resultant cell surface pheno-

Another factor to consider is genetic predisposition or health status of the patients whereby some, with for example, autoimmune disease or allergies and a preponderance of Th17 or Th1/Th2 cells respectively may be more at risk, with the resultant tumour phenotype dependent on this. In evidence, at least for BIA-ALCL Th1, Th2 and Th17 origins have been proposed based on the profile of secreted cytokines and expression of specific transcription factors, although of course none of these factors in isolation are necessarily truly indicative of the cell of origin, and as mentioned before, the contribution of the microenvironment cannot be

The common expression of CD30 on all entities of ALCL is suggestive of an infectious aetiology whereby activation of the underlying T cells triggers expression of this cell surface protein. However, individual cell surface proteins in isolation are not necessarily indicative of the cell of origin of any given cancer, which combined with the propensity of cancer cells to aberrantly up- or down-regulate expression of proteins according to evolutionary fitness necessitates further evidence to draw conclusive decisions. Yet, in evidence of an infectious aetiology,

*Proposed mechanisms of tumorigenesis for ALCL. Data suggest that the NPM-ALK generating chromosomal translocation occurs in primitive haemopoietic cells, such as early thymic progenitors, whereby aberrant TCR rearrangements are tolerated [30]. Incipient tumour cells then exit into the periphery where secondary events lead to transformation. Conversely, systemic ALCL, ALK−, pcALCL and BIA-ALCL more likely initiate in circulating peripheral T cells whereby chronic antigenic stimulation mediated by infectious agents, an inflammatory milieu and/or toxic insult leads to the acquisition of malignancy-promoting mutations and* 

#### *Anaplastic Large Cell Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.81382*

*Peripheral T-cell Lymphomas*

effects will be limited [123].

**histopathology?**

disease pathogenesis as discussed below [30].

**6.1 Cell of origin**

agents.

Indeed, biological studies have identified a number of potential therapeutic targets, which in some cases, and with time, have been matched to available drugs. However, with relatively few patients, coupled with a good prognosis, at least for children with ALK+ systemic disease, it is difficult to formulate trials to test these

**6. The origins and pathogenesis of ALCL: a common origin with distinct pathogenesis or different origins converging on a shared** 

Systemic ALCL presents in the periphery suggestive of a peripheral T cell origin, although as many as 50% of children show mediastinal involvement [29]. In this latter vein, a thymic origin has been proposed whereby gene expression signatures associated with early thymic progenitors (ETP) are detected in ALCL cancer stem cells, in fitting with the detection of transcripts for the t(2;5)(p23;q35) translocation breakpoint product in 2% of cord blood specimens from healthy babies [124, 125]. In addition, studies of epigenetic signatures are in keeping with an ETP origin [49]. As such, it is not inconceivable that ALCL, ALK+ has a thymic, perhaps *in utero* origin in-line with the pathogenesis of paediatric leukaemias [29]. Additionally, this is in keeping with a paediatric presentation and the early-life involution of the thymus. Furthermore, studies of murine models show that events in the periphery once incipient tumour cells emerge from the thymus contribute to

While ALCL, ALK+ is proposed to emerge from the thymus, a similar origin likely does not apply to ALK-negative disease, including pcALCL, BIA-ALCL and ALCL, ALK−. In these latter cases, circulating peripheral T cells are most probably the cells of origin given the older age of diagnosis and peripheral location, particularly with regards to BIA-ALCL and pcALCL. If this is the case, if the type of T cell that becomes transformed can be identified, this may give clues as to disease pathogenesis. While histopathology indicating an activated CD30-expressing T cell producing cytotoxic proteins, yet also often retaining CD4 expression, has given rise to a presumed cytotoxic T cell origin, recent data challenges this perception [29, 126]. Specifically, analysis of gene expression data suggests a Th17 origin, a T cell that usually responds to large extracellular infectious agents such as bacteria and is often implicated in autoimmune disease [89, 127]. However, given that ALCL often lack expression of TCR-related signalling proteins as well as a functional cell surface TCR, analogies to innate lymphoid cells (ILC), specifically ILC type 3 cells are also apparent [127]. Naturally, the eventual cell phenotype is not necessarily reflective of the cell of origin with environmental events likely contributing to the final observed identity. In this regard, whether in ALCL, ALK+ this is shaped by ALKmediated activities (or is the consequence of other induced (epi)genetic events) remains to be fully elucidated as it does for other ALCL sub-types. In evidence, it has been shown that NPM-ALK induces expression of cytotoxic proteins suggesting that their presence reflects the activities of this inherent transforming event rather than a property of the cell of origin, at least for ALCL, ALK+ [128]. This would

A further approach given the immune response to ALK in patients with ALKpositive disease, is a vaccination strategy [122]. This is especially relevant as ALK expression seems to be limited to tissues of neonatal origin suggesting that side-

**28**

partly explain the 'confused' T cell phenotype with both helper and cytotoxic T cell properties apparent. Indeed, plasticity amongst helper T cell subsets is immense and is dependent on the relative expression levels of key transcription factors such as T-bet, RORγ, GATA-3 and Foxp3 as well as cytokines in the microenvironment [129]. Hence, for a T cell aberrantly expressing a variety of genetic changes, embedded in specific inflammatory microenvironments, the resultant cell surface phenotype may no longer reflect the cell of origin.

Another factor to consider is genetic predisposition or health status of the patients whereby some, with for example, autoimmune disease or allergies and a preponderance of Th17 or Th1/Th2 cells respectively may be more at risk, with the resultant tumour phenotype dependent on this. In evidence, at least for BIA-ALCL Th1, Th2 and Th17 origins have been proposed based on the profile of secreted cytokines and expression of specific transcription factors, although of course none of these factors in isolation are necessarily truly indicative of the cell of origin, and as mentioned before, the contribution of the microenvironment cannot be discounted [88–90].

## **6.2 An infectious aetiology?**

The common expression of CD30 on all entities of ALCL is suggestive of an infectious aetiology whereby activation of the underlying T cells triggers expression of this cell surface protein. However, individual cell surface proteins in isolation are not necessarily indicative of the cell of origin of any given cancer, which combined with the propensity of cancer cells to aberrantly up- or down-regulate expression of proteins according to evolutionary fitness necessitates further evidence to draw conclusive decisions. Yet, in evidence of an infectious aetiology,

#### **Figure 2.**

*Proposed mechanisms of tumorigenesis for ALCL. Data suggest that the NPM-ALK generating chromosomal translocation occurs in primitive haemopoietic cells, such as early thymic progenitors, whereby aberrant TCR rearrangements are tolerated [30]. Incipient tumour cells then exit into the periphery where secondary events lead to transformation. Conversely, systemic ALCL, ALK−, pcALCL and BIA-ALCL more likely initiate in circulating peripheral T cells whereby chronic antigenic stimulation mediated by infectious agents, an inflammatory milieu and/or toxic insult leads to the acquisition of malignancy-promoting mutations and cellular transformation.*

sALCL have been reported in the context of insect and tick bites, as well as bacterial infections on the surface of breast implants in BIA-ALCL and in association with cutaneous T cell lymphomas whereby TLRs 2, 4 and 7 are expressed by tumour cells [130–132]. Such infectious aetiologies would also produce an inflammatory microenvironment dictated by the infectious agent whereby cytokines, growth factors and many cell types involved in inflammation would be present and may contribute to disease pathogenesis. In this regard, the lymphohistiocytic subtype of sALCL is, as its name suggests, infiltrated with macrophages and many cytokines have been detected at elevated levels in patients diagnosed with ALCL, ALK+ [26, 133] (**Figure 2**).

## **7. Conclusions**

ALCL is a diverse disease entity affecting a range of patients ranging from children to women with breast implants. What is clear, is that all ALCL share some common immunohistopathological features, most prominently CD30 expression, but the clinical courses of these diseases vary considerably from the indolent LPD, pcALCL through to aggressive, poor prognostic malignancies such as sALCL, ALK−. Our understanding of the underlying biology is improving year on year and has had a significant impact on clinical decision making including therapeutic approaches. While for many forms of ALCL, therapy has not altered considerably over the past decade, novel targeted approaches to treatment are entering the clinical arena ranging from monoclonal antibodies to kinase inhibitors. Indeed, we are now in the fortunate position whereby there are a plethora of therapeutic agents, but too few patients to trial them.

## **Acknowledgements**

I would like to acknowledge all authors that have contributed to our understanding of ALCL who could not be cited due to page length restrictions.

**31**

**Author details**

Suzanne D. Turner

provided the original work is properly cited.

\*Address all correspondence to: sdt36@cam.ac.uk

*Anaplastic Large Cell Lymphoma*

*DOI: http://dx.doi.org/10.5772/intechopen.81382*

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Pathology, University of Cambridge, Cambridge, UK

## **Conflict of interest**

The author declares no conflicts of interest.

*Anaplastic Large Cell Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.81382*

*Peripheral T-cell Lymphomas*

ALK+ [26, 133] (**Figure 2**).

patients to trial them.

**Acknowledgements**

**Conflict of interest**

**7. Conclusions**

sALCL have been reported in the context of insect and tick bites, as well as bacterial infections on the surface of breast implants in BIA-ALCL and in association with cutaneous T cell lymphomas whereby TLRs 2, 4 and 7 are expressed by tumour cells [130–132]. Such infectious aetiologies would also produce an inflammatory microenvironment dictated by the infectious agent whereby cytokines, growth factors and many cell types involved in inflammation would be present and may contribute to disease pathogenesis. In this regard, the lymphohistiocytic subtype of sALCL is, as its name suggests, infiltrated with macrophages and many cytokines have been detected at elevated levels in patients diagnosed with ALCL,

ALCL is a diverse disease entity affecting a range of patients ranging from children to women with breast implants. What is clear, is that all ALCL share some common immunohistopathological features, most prominently CD30 expression, but the clinical courses of these diseases vary considerably from the indolent LPD, pcALCL through to aggressive, poor prognostic malignancies such as sALCL, ALK−. Our understanding of the underlying biology is improving year on year and has had a significant impact on clinical decision making including therapeutic approaches. While for many forms of ALCL, therapy has not altered considerably over the past decade, novel targeted approaches to treatment are entering the clinical arena ranging from monoclonal antibodies to kinase inhibitors. Indeed, we are now in the fortunate position whereby there are a plethora of therapeutic agents, but too few

I would like to acknowledge all authors that have contributed to our understand-

ing of ALCL who could not be cited due to page length restrictions.

The author declares no conflicts of interest.

**30**

## **Author details**

Suzanne D. Turner Department of Pathology, University of Cambridge, Cambridge, UK

\*Address all correspondence to: sdt36@cam.ac.uk

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Plast Surg; 2018

2017;**139**(1):1-9

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2017;**37**(3):285-289

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*Peripheral T-cell Lymphomas*

[64] Liu C et al. MicroRNA expression

www.fda.gov/MedicalDevices/ ProductsandMedicalProcedures/

BreastImplants/ucm239996.htm

[72] Ministere des affaires sociales, d.l.s.e.d.d.d.f., La France reste vigilante pour detecter rapidement les cas de lymphomes parmi les femmes porteuses

[73] Administration, U.F.a.D., Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL). 2017

[74] Antonella C, Rosaria B, Marcella M. 22 cases of BIA-ALCL: Awareness and outcome tracking from the Italian Ministry of Health. Plastic and

ImplantsandProsthetics/

d'implants mammaires. 2015

Reconstructive Surgery. 2017

2017;**43**(8):1393-1401

[76] de Jong D et al. Anaplastic large-cell lymphoma in women with breast implants. JAMA. 2008;**300**(17):2030-2035

[77] Laurent C et al. Breast implant-associated anaplastic large cell lymphoma: Two distinct clinicopathological variants with

2016;**27**(2):306-314

different outcomes. Annals of Oncology.

[78] Clemens MW, Miranda RN. Coming

[79] Doren EL et al. U.S. epidemiology

of age: Breast implant-associated anaplastic large cell lymphoma after 18 years of investigation. Clinics in Plastic

Surgery. 2015;**42**(4):605-613

of breast implant-associated anaplastic large cell lymphoma. Plastic and Reconstructive Surgery.

2017;**139**(5):1042-1050

[75] Johnson L et al. Breast implant associated anaplastic large cell lymphoma: The UK experience. Recommendations on its management and implications for informed consent. European Journal of Surgical Oncology.

signatures associated with anaplastic

[65] Piva R et al. Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. Journal of Clinical Oncology.

[66] Piccaluga PP et al. Molecular profiling improves classification and prognostication of nodal

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[67] Agnelli L et al. Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma. Blood.

[68] Iqbal J et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma.

profiling identifies molecular

large cell lymphoma. Blood. 2013;**122**(12):2083-2092

2010;**28**(9):1583-1590

2013;**31**(24):3019-3025

2012;**120**(6):1274-1281

Blood. 2010;**115**(5):1026-1036

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U.F.a.D. Anaplastic large cell lymphoma (ALCL) in women with breast implants: Preliminary findings and analyses. 2011. Available from: http://wayback.archive-it. org/7993/20171115053750/https:/

1997;**100**(2):554-555

[71] Administration,

**36**

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[85] Clemens MW, Horwitz SM. NCCN consensus guidelines for the diagnosis and management of breast implantassociated anaplastic large cell lymphoma. Aesthetic Surgery Journal. 2017;**37**(3):285-289

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[87] Ye X et al. Anaplastic large cell lymphoma (ALCL) and breast implants: Breaking down the evidence. Mutation Research, Reviews in Mutation Research. 2014;**762**:123-132

[88] Lechner MG et al. Survival signals and targets for therapy in breast implant-associated ALK—Anaplastic large cell lymphoma. Clinical Cancer Research. 2012;**18**(17):4549-4559

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[90] Kadin ME et al. IL-13 is produced by tumor cells in breast implant associated anaplastic large cell lymphoma: Implications for pathogenesis. Human Pathology. 2018 Aug;**78**:54-62. DOI: 10.1016/j.humpath.2018.04.007. Epub 2018 Apr 22

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[92] Di Napoli A et al. Targeted next generation sequencing of breast implant-associated anaplastic large cell lymphoma reveals mutations in JAK/STAT signalling pathway genes, TP53 and DNMT3A. British Journal of Haematology. 2018;**180**(5):741-744

[93] Bekkenk MW et al. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: A report from the Dutch cutaneous lymphoma group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood. 2000;**95**(12):3653-3661

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Dermatology. 2003;**49**(6):

1049-1058

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Oncology. Journal of Clinical Oncology.

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[108] Melchers RC et al. Evaluation of treatment results in multifocal primary cutaneous anaplastic large cell lymphoma: Report of the Dutch Cutaneous Lymphoma Group. The British Journal of Dermatology. 2018 Sep;**179**(3):724-731. DOI: 10.1111/ bjd.16501. Epub 2018 Jun 21

Biology. 2013;**973**:197-212

2012;**21**(8):632-634

2009;**31**(2):145-147

2009;**27**(30):5056-5061

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2018;**6**(4):634-637

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[97] Kiran T et al. The significance of MUM1/IRF4 protein expression and IRF4 translocation of CD30(+) cutaneous T-cell lymphoproliferative disorders: A study of 53 cases. Leukemia

Research. 2013;**37**(4):396-400

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2011;**24**(4):596-605

2010;**130**(3):816-825

2009;**23**(3):574-580

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**38**

primary cutaneous anaplastic large cell lymphoma: A report of the Dutch cutaneous lymphoma group. International Journal of Radiation Oncology, Biology, Physics. 2017;**99**(5):1279-1285

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[112] Mosse YP et al. Targeting ALK with Crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: A Children's oncology group study. Journal of Clinical Oncology. 2017;**35**(28):3215-3221

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[114] Senter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nature Biotechnology. 2012;**30**(7):631-637

[115] Nielson C et al. Loss of CD30 expression in anaplastic large cell lymphoma following brentuximab therapy. Journal of Drugs in Dermatology. 2016;**15**(7): 894-895

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[117] Pro B et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic largecell lymphoma: Results of a phase II study. Journal of Clinical Oncology. 2012;**30**(18):2190-2196

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[119] Pro B et al. Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood. 2017;**130**(25):2709-2717

[120] Laimer D et al. PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas. Nature Medicine. 2012;**18**(11):1699-1704

[121] Chen J et al. Cytokine receptor signaling is required for the survival of ALK− anaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations. Proceedings of the National Academy of Sciences of the United States of America. 2017;**114**(15):3975-3980

[122] Chiarle R et al. The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination. Nature Medicine. 2008;**14**(6): 676-680

[123] Pulford K et al. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood. 1997;**89**(4):1394-1404

[124] Moti N et al. Anaplastic large cell lymphoma-propagating cells are detectable by side population analysis and possess an expression profile reflective of a primitive origin. Oncogene. 2015 Apr 2;**34**(14):1843- 1852. DOI: 10.1038/onc.2014.112. Epub 2014 May 12

[125] Laurent C et al. Circulating t(2;5) positive cells can be detected in cord blood of healthy newborns. Leukemia. 2012;**26**(1):188-190

[126] Kasprzycka M et al. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**(26):9964-9969

[127] Schleussner N et al. The AP-1- BATF and -BATF3 module is essential for growth, survival and TH17/ ILC3 skewing of anaplastic large cell lymphoma. Leukemia. 2018 Sep;**32**(9):1994-2007. DOI: 10.1038/ s41375-018-0045-9. Epub 2018 Mar 28

[128] Pearson JD et al. NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma. International Journal of Clinical and Experimental Pathology. 2011;**4**(2):124-133

[129] Tripathi SK, Lahesmaa R. Transcriptional and epigenetic regulation of T-helper lineage specification. Immunological Reviews. 2014;**261**(1):62-83

[130] Lamant L et al. Cutaneous presentation of ALK-positive anaplastic large cell lymphoma following insect bites: Evidence for an association

in five cases. Haematologica. 2010;**95**(3):449-455

[131] Piccaluga PP et al. Anaplastic lymphoma kinase expression as a marker of malignancy. Application to a case of anaplastic large cell lymphoma with huge granulomatous reaction. Haematologica. 2000;**85**(9):978-981

[132] Hu H et al. Bacterial biofilm infection detected in breast implantassociated anaplastic large-cell lymphoma. Plastic and Reconstructive Surgery. 2016;**137**(6):1659-1669

[133] Knorr F et al. Blood cytokine concentrations in pediatric patients with anaplastic lymphoma kinasepositive anaplastic large cell lymphoma. Haematologica. 2018;**103**(3):477-485

[134] Hernandez L et al. Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: Identification of a new TFG-ALK(XL) chimeric gene with transforming activity. The American Journal of Pathology. 2002;**160**(4):1487-1494

[135] Hernandez L et al. TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. Blood. 1999;**94**(9):3265-3268

[136] Lamant L et al. A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2) (q25;p23) translocation. Blood. 1999;**93**(9):3088-3095

[137] Wlodarska I et al. The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma. Blood. 1998;**92**(8):2688-2695

[138] Ma Z et al. Inv(2)(p23q35) in anaplastic large-cell lymphoma induces

**41**

*Anaplastic Large Cell Lymphoma*

[139] Tort F et al. Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Laboratory Investigation.

2001;**81**(3):419-426

2002;**34**(4):354-362

[141] Touriol C et al. Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). Blood.

2000;**95**(10):3204-3207

Cancer. 2003;**37**(4):427-432

2000;**157**(2):377-384

[143] Lawrence B et al. TPM3-ALK and TPM4-ALK oncogenes in

inflammatory myofibroblastic tumors. The American Journal of Pathology.

[144] van, der Krogt JA et al. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene. Haematologica. 2017;**102**(9):1605-1616

[142] Lamant L et al. Non-muscle myosin heavy chain (MYH9): A new partner fused to ALK in anaplastic large cell lymphoma. Genes, Chromosomes &

*DOI: http://dx.doi.org/10.5772/intechopen.81382*

constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis. Blood. 2000;**95**(6):2144-2149

[140] Cools J et al. Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes, Chromosomes & Cancer.

*Anaplastic Large Cell Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.81382*

*Peripheral T-cell Lymphomas*

1997;**89**(4):1394-1404

2014 May 12

2012;**26**(1):188-190

[126] Kasprzycka M et al.

monoclonal antibody ALK1. Blood.

in five cases. Haematologica.

[131] Piccaluga PP et al. Anaplastic lymphoma kinase expression as a marker of malignancy. Application to a case of anaplastic large cell lymphoma with huge granulomatous reaction. Haematologica. 2000;**85**(9):978-981

[132] Hu H et al. Bacterial biofilm infection detected in breast implantassociated anaplastic large-cell

Surgery. 2016;**137**(6):1659-1669

[133] Knorr F et al. Blood cytokine concentrations in pediatric patients with anaplastic lymphoma kinasepositive anaplastic large cell lymphoma. Haematologica. 2018;**103**(3):477-485

[134] Hernandez L et al. Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: Identification of a new TFG-ALK(XL) chimeric gene with transforming activity. The American Journal of Pathology.

[135] Hernandez L et al. TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. Blood.

[136] Lamant L et al. A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2) (q25;p23) translocation. Blood.

[137] Wlodarska I et al. The cryptic inv(2)(p23q35) defines a new molecular

genetic subtype of ALK-positive anaplastic large-cell lymphoma. Blood.

[138] Ma Z et al. Inv(2)(p23q35) in anaplastic large-cell lymphoma induces

2002;**160**(4):1487-1494

1999;**94**(9):3265-3268

1999;**93**(9):3088-3095

1998;**92**(8):2688-2695

lymphoma. Plastic and Reconstructive

2010;**95**(3):449-455

[124] Moti N et al. Anaplastic large cell lymphoma-propagating cells are detectable by side population analysis and possess an expression profile reflective of a primitive origin. Oncogene. 2015 Apr 2;**34**(14):1843- 1852. DOI: 10.1038/onc.2014.112. Epub

[125] Laurent C et al. Circulating t(2;5) positive cells can be detected in cord blood of healthy newborns. Leukemia.

Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**(26):9964-9969

[127] Schleussner N et al. The AP-1- BATF and -BATF3 module is essential for growth, survival and TH17/ ILC3 skewing of anaplastic large cell lymphoma. Leukemia. 2018 Sep;**32**(9):1994-2007. DOI: 10.1038/ s41375-018-0045-9. Epub 2018 Mar 28

[128] Pearson JD et al. NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma. International Journal of Clinical and Experimental Pathology.

[129] Tripathi SK, Lahesmaa R. Transcriptional and epigenetic regulation of T-helper lineage

[130] Lamant L et al. Cutaneous

specification. Immunological Reviews.

presentation of ALK-positive anaplastic large cell lymphoma following insect bites: Evidence for an association

2011;**4**(2):124-133

2014;**261**(1):62-83

**40**

constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis. Blood. 2000;**95**(6):2144-2149

[139] Tort F et al. Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Laboratory Investigation. 2001;**81**(3):419-426

[140] Cools J et al. Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes, Chromosomes & Cancer. 2002;**34**(4):354-362

[141] Touriol C et al. Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). Blood. 2000;**95**(10):3204-3207

[142] Lamant L et al. Non-muscle myosin heavy chain (MYH9): A new partner fused to ALK in anaplastic large cell lymphoma. Genes, Chromosomes & Cancer. 2003;**37**(4):427-432

[143] Lawrence B et al. TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. The American Journal of Pathology. 2000;**157**(2):377-384

[144] van, der Krogt JA et al. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene. Haematologica. 2017;**102**(9):1605-1616

**43**

**Chapter 4**

**Abstract**

hepatosplenic

**1. Introduction**

**2.1 General features**

*Silvana Novelli*

other extranodal NK/T lymphomas.

Extranodal T/NK Lymphomas

**Keywords:** extranodal lymphoma, NK/T-cell lymphoma, NK lymphoma,

In this chapter, the majority of extranodal T/NK lymphomas will be discussed proportionally to the amount of available evidence and its clinical relevance. The 2016 WHO classification [1] includes the following entities: extranodal NK/T-cell lymphoma nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, intestinal T-cell lymphoma NOS, and hepatosplenic T-cell lymphoma. In general, these are very infrequent and aggressive lymphomas, being the most prevalent the extranodal NK/T-cell lymphoma, nasal type. The current classification separates enteropathy-associated T-cell lymphoma from monomorphic epitheliotropic intestinal T-cell lymphoma in two different entities; in this way, intestinal T-cell lymphoma NOS remains a category to place unclassifiable histologies. Recent advances in gene expression profiling have allowed identify genes and proteins with potential role in pathogenesis. Collaboration between different centers is showing promising results that will surely modify and improve current treatments and progno-

sis. It will also help to increase the evidence in the new classification categories.

Natural killer (NK) neoplasias are divided into extranodal NK/T, nasal type, and NK aggressive leukemia. The "nasal type" distinction is explained because there is a predominant affection of nasal zone, nasopharynx, and upper respiratory airways (60–90% of cases). The "extra-nasal" type also exists but is infrequent; it affects

**2. Extranodal NK/T-cell lymphoma, nasal type (ENKL)**

non-nasal areas such as the skin, testicles, intestines, and muscles [2].

Extranodal T/NK lymphomas comprise infrequent and highly aggressive entities such as extranodal NK/T-cell lymphoma nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, intestinal T-cell lymphoma NOS, and hepatosplenic T-cell lymphoma. Except for NK/T lymphoma nasal type, there is scarce evidence to support a specific therapeutic regimen in first line and relapse. As the only potentially curative therapy is allogeneic hematopoietic stem cell transplantation, it should be assessed in relapsing/ refractory NK/T lymphoma nasal type and in the first line after remission in the

## **Chapter 4** Extranodal T/NK Lymphomas

*Silvana Novelli*

## **Abstract**

Extranodal T/NK lymphomas comprise infrequent and highly aggressive entities such as extranodal NK/T-cell lymphoma nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, intestinal T-cell lymphoma NOS, and hepatosplenic T-cell lymphoma. Except for NK/T lymphoma nasal type, there is scarce evidence to support a specific therapeutic regimen in first line and relapse. As the only potentially curative therapy is allogeneic hematopoietic stem cell transplantation, it should be assessed in relapsing/ refractory NK/T lymphoma nasal type and in the first line after remission in the other extranodal NK/T lymphomas.

**Keywords:** extranodal lymphoma, NK/T-cell lymphoma, NK lymphoma, hepatosplenic

## **1. Introduction**

In this chapter, the majority of extranodal T/NK lymphomas will be discussed proportionally to the amount of available evidence and its clinical relevance. The 2016 WHO classification [1] includes the following entities: extranodal NK/T-cell lymphoma nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, intestinal T-cell lymphoma NOS, and hepatosplenic T-cell lymphoma. In general, these are very infrequent and aggressive lymphomas, being the most prevalent the extranodal NK/T-cell lymphoma, nasal type. The current classification separates enteropathy-associated T-cell lymphoma from monomorphic epitheliotropic intestinal T-cell lymphoma in two different entities; in this way, intestinal T-cell lymphoma NOS remains a category to place unclassifiable histologies. Recent advances in gene expression profiling have allowed identify genes and proteins with potential role in pathogenesis. Collaboration between different centers is showing promising results that will surely modify and improve current treatments and prognosis. It will also help to increase the evidence in the new classification categories.

## **2. Extranodal NK/T-cell lymphoma, nasal type (ENKL)**

## **2.1 General features**

Natural killer (NK) neoplasias are divided into extranodal NK/T, nasal type, and NK aggressive leukemia. The "nasal type" distinction is explained because there is a predominant affection of nasal zone, nasopharynx, and upper respiratory airways (60–90% of cases). The "extra-nasal" type also exists but is infrequent; it affects non-nasal areas such as the skin, testicles, intestines, and muscles [2].

#### *Peripheral T-cell Lymphomas*

Several works have tried to identify biologic differences between both clinical manifestations but it has not been possible. The "extra-nasal" variant has a worse outcome; patients frequently present with B symptoms, advanced stages, hemophagocytosis, and cytopenias.

Unlike Asia and Latin America, ENKL is infrequent in our media representing approximately 2% of non-Hodgkin lymphomas [3].

#### **2.2 Etiology**

Epstein-Barr virus (EBV) is an important feature of ENKL [4]. More than 90% of reported cases were positive for EBNA-1 and EBER-1. EBV is present in an episomal form not integrated into the host DNA, with type II latency [5, 6].

## **2.3 Diagnosis**

At the morphological level, angiocentric and angio-invasive infiltrates composed of small-medium-sized atypical lymphocytes with irregular nuclei and immunoblasts are evident. There is a variable infiltration of plasma cells and, to a lesser extent, of eosinophils and histiocytes. The presence of extensive necrosis is frequent.

By immunohistochemistry, the tumor NK cells can have two lines of origin: NK line (65–75% of cases): CD2 (+), CD3-ε (+) cytoplasmic, CD56 (+/−),

CD94 (+), cytotoxic markers (TIA, GZM-B, perforin) (+), and TCR-β (BF1) (−).

True T-line (25–35% of cases): CD2 (+), CD3-ε (+), CD5 (+), CD8 (+/−), TCR-β (BF1) (+), CD56 (−/+), and cytotoxic markers (+).

EBV is detected in almost all cases by in situ hybridization (EBER) and by Southern blot. The latent EBV membrane protein has a variable expression, so it is not advisable to detect the virus [7].

Early chromosomal examinations recognized del(6)(q21q25) as a repetitive chromosomal anomaly in ENKL. In view of investigations of 6q, including gene expression profiling (GEP), PRDM1, FOXO3, and PTPRK were recognized as putative tumor suppressor genes. A high expression of genes of cytotoxic molecules such as granzyme H and deregulation of the NF-κB, AKT, and JAK-STAT3 pathways were also present in ENKL. Half of the patients have mutations in *FAS* and <50% in *TP53*. *DDX3X* and *BCL6* are also mutated; the former was more frequently mutated in men and was associated with poor survival [8].

## **2.4 Staging and prognosis**

Because the prognosis is different between the "nasal" and the "extranasal" variants, techniques to detect occult disease become clinically important.

It is advisable to use PET/CT since it has shown greater sensitivity. In those cases where there is evidence of involvement of the central nervous system, it is necessary to consider complementing the study with magnetic resonance imaging (MRI) [9, 10].

Bone marrow biopsy is part of staging and cannot yet be replaced by the extensive use of PET/CT in this entity [11].

The staging should be performed according to Ann Arbor since most clinical trials have established it that way. However, TNM staging is also widely used since it offers the advantage of better assessing tumor size and infiltration of adjacent organs and tissues of the localized stage [12].

The ENKL prognostic index includes both stage and other variables. This index is fundamental for decision-making [13].

The ENKL index punctuates the presence of "B" symptoms, Ann Arbor stage ≥III, LDH ≥1 × upper normal limit, and regional lymph nodes (N1-N3, not M1) involvement

**45**

*Extranodal T/NK Lymphomas*

impairs survival (see **Table 1**).

*OS, overall survival; RR, relative risk.*

*Survival and relative risk of death.*

ever possible [14, 15].

**2.5 Treatment**

**Table 1.**

30 mg/m2

ifosfamide 1200 mg/m<sup>2</sup>

49%, *p* < 0.001) [20].

the patient.

*DOI: http://dx.doi.org/10.5772/intechopen.85541*

according to the TNM staging system. Every point increases the relative of death and

**Risk group Number of factors % 5-year OS RR of death** Group 1 0 81 1 Group 2 1 64 1.8 Group 3 2 34 4.1 Group 4 3–4 7 13.6

The treatment is planned according to the stage and the risk.

response rate was 81% (77% complete response, CR) [18].

3 years were 85 and 86%, respectively [19].

glycoprotein-P schemes have been designed.

The viral quantification of EBV is useful to assess the tumor burden. Negative loads have a better prognosis than cases with low EBV load (<1000 copies/ml in plasma or <100 copies/mcg of mononuclear cell DNA) and that of high load. It is also useful to monitor the response to therapy. Therefore, it should be done when-

In patients with stages I–II and low risk, radiotherapy (≥54 Gy) is the best option. It has not been observed that adding chemotherapy improves the prognosis [2, 16, 17]. If we focus on cases with stages I–II, but intermediate risk and high risk, it has been

Another study showed similar results. Radiotherapy (40–52.8 Gy) and cisplatin

Also for stages IE–IIE (all risk groups), the DICE–L-asparaginase chemotherapy with radiotherapy (45 Gy) after four cycles vs. radiotherapy alone has been tested The CR rate was higher for patients in the sequential radiotherapy group (90.9%) than in the radiotherapy group (77.8%; *p* = 0.124). PFS and OS at 5 years after diagnosis were significantly higher for patients in the chemo-radiotherapy group (PFS: 89%; OS: 82%) than in the radiotherapy group (PFS: 49%, *p <* 0.001; OS:

In advanced stages, the treatment must take into account the functional status of

If the patient's general condition allows it (ECOG 0–2) and the patient is a candidate

for an autologous hematopoietic stem cell transplant (ASCT), the first-line therapy will be the SMILE scheme followed by TASP (dexamethasone: 40 mg EV or oral, days

days 1–3,

days 1–3, and dexamethasone

weekly followed by three cycles of VIPD (etoposide 100 mg/m2

days 1–3, cisplatin 33 mg/m2

40 mg days 1–4). The progression-free survival (PFS) and the OS estimated at

ENKL is associated with a high expression of P glycoprotein that confers resistance to most anthracycline-based regimens. For this reason, non-dependent

The regimens that have demonstrated greater efficacy are based on

L-asparaginase. However, they are associated with a high toxicity.

shown that the best option is the combination of chemotherapy and radiotherapy. In the JCOG0211 study, radiotherapy (50 Gy) and three cycles of dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) were administered. The overall survival (OS) at 2 years was 78% (95% CI, 57–89%). It was compared with a historical control of patients treated only with radiotherapy (OS 45%). The overall

#### *Extranodal T/NK Lymphomas DOI: http://dx.doi.org/10.5772/intechopen.85541*


#### **Table 1.**

*Peripheral T-cell Lymphomas*

phagocytosis, and cytopenias.

**2.2 Etiology**

**2.3 Diagnosis**

approximately 2% of non-Hodgkin lymphomas [3].

Several works have tried to identify biologic differences between both clinical manifestations but it has not been possible. The "extra-nasal" variant has a worse outcome; patients frequently present with B symptoms, advanced stages, hemo-

Unlike Asia and Latin America, ENKL is infrequent in our media representing

Epstein-Barr virus (EBV) is an important feature of ENKL [4]. More than 90% of reported cases were positive for EBNA-1 and EBER-1. EBV is present in an episomal form not integrated into the host DNA, with type II latency [5, 6].

At the morphological level, angiocentric and angio-invasive infiltrates composed of small-medium-sized atypical lymphocytes with irregular nuclei and immunoblasts are evident. There is a variable infiltration of plasma cells and, to a lesser extent, of

By immunohistochemistry, the tumor NK cells can have two lines of origin: NK line (65–75% of cases): CD2 (+), CD3-ε (+) cytoplasmic, CD56 (+/−), CD94 (+), cytotoxic markers (TIA, GZM-B, perforin) (+), and TCR-β (BF1) (−). True T-line (25–35% of cases): CD2 (+), CD3-ε (+), CD5 (+), CD8 (+/−),

EBV is detected in almost all cases by in situ hybridization (EBER) and by Southern blot. The latent EBV membrane protein has a variable expression, so it is

Early chromosomal examinations recognized del(6)(q21q25) as a repetitive chromosomal anomaly in ENKL. In view of investigations of 6q, including gene expression profiling (GEP), PRDM1, FOXO3, and PTPRK were recognized as putative tumor suppressor genes. A high expression of genes of cytotoxic molecules such as granzyme H and deregulation of the NF-κB, AKT, and JAK-STAT3 pathways were also present in ENKL. Half of the patients have mutations in *FAS* and <50% in *TP53*. *DDX3X* and *BCL6* are also mutated; the former was more frequently mutated

Because the prognosis is different between the "nasal" and the "extranasal" vari-

It is advisable to use PET/CT since it has shown greater sensitivity. In those cases where there is evidence of involvement of the central nervous system, it is necessary to consider complementing the study with magnetic resonance imaging (MRI) [9, 10]. Bone marrow biopsy is part of staging and cannot yet be replaced by the exten-

The staging should be performed according to Ann Arbor since most clinical trials have established it that way. However, TNM staging is also widely used since it offers the advantage of better assessing tumor size and infiltration of adjacent

The ENKL prognostic index includes both stage and other variables. This index

The ENKL index punctuates the presence of "B" symptoms, Ann Arbor stage ≥III, LDH ≥1 × upper normal limit, and regional lymph nodes (N1-N3, not M1) involvement

ants, techniques to detect occult disease become clinically important.

eosinophils and histiocytes. The presence of extensive necrosis is frequent.

TCR-β (BF1) (+), CD56 (−/+), and cytotoxic markers (+).

in men and was associated with poor survival [8].

not advisable to detect the virus [7].

**2.4 Staging and prognosis**

sive use of PET/CT in this entity [11].

organs and tissues of the localized stage [12].

is fundamental for decision-making [13].

**44**

*Survival and relative risk of death.*

according to the TNM staging system. Every point increases the relative of death and impairs survival (see **Table 1**).

The viral quantification of EBV is useful to assess the tumor burden. Negative loads have a better prognosis than cases with low EBV load (<1000 copies/ml in plasma or <100 copies/mcg of mononuclear cell DNA) and that of high load. It is also useful to monitor the response to therapy. Therefore, it should be done whenever possible [14, 15].

#### **2.5 Treatment**

The treatment is planned according to the stage and the risk.

In patients with stages I–II and low risk, radiotherapy (≥54 Gy) is the best option. It has not been observed that adding chemotherapy improves the prognosis [2, 16, 17].

If we focus on cases with stages I–II, but intermediate risk and high risk, it has been shown that the best option is the combination of chemotherapy and radiotherapy.

In the JCOG0211 study, radiotherapy (50 Gy) and three cycles of dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) were administered. The overall survival (OS) at 2 years was 78% (95% CI, 57–89%). It was compared with a historical control of patients treated only with radiotherapy (OS 45%). The overall response rate was 81% (77% complete response, CR) [18].

Another study showed similar results. Radiotherapy (40–52.8 Gy) and cisplatin 30 mg/m2 weekly followed by three cycles of VIPD (etoposide 100 mg/m2 days 1–3, ifosfamide 1200 mg/m<sup>2</sup> days 1–3, cisplatin 33 mg/m2 days 1–3, and dexamethasone 40 mg days 1–4). The progression-free survival (PFS) and the OS estimated at 3 years were 85 and 86%, respectively [19].

ENKL is associated with a high expression of P glycoprotein that confers resistance to most anthracycline-based regimens. For this reason, non-dependent glycoprotein-P schemes have been designed.

The regimens that have demonstrated greater efficacy are based on L-asparaginase. However, they are associated with a high toxicity.

Also for stages IE–IIE (all risk groups), the DICE–L-asparaginase chemotherapy with radiotherapy (45 Gy) after four cycles vs. radiotherapy alone has been tested The CR rate was higher for patients in the sequential radiotherapy group (90.9%) than in the radiotherapy group (77.8%; *p* = 0.124). PFS and OS at 5 years after diagnosis were significantly higher for patients in the chemo-radiotherapy group (PFS: 89%; OS: 82%) than in the radiotherapy group (PFS: 49%, *p <* 0.001; OS: 49%, *p* < 0.001) [20].

In advanced stages, the treatment must take into account the functional status of the patient.

If the patient's general condition allows it (ECOG 0–2) and the patient is a candidate for an autologous hematopoietic stem cell transplant (ASCT), the first-line therapy will be the SMILE scheme followed by TASP (dexamethasone: 40 mg EV or oral, days

2–4; methotrexate: 2000 mg/m2 EV, day 1; ifosfamide: 1500 mg/m2 EV, days 2–4; *E. coli* L-asparaginase: 6000 U/m2 EV, days 8, 10, 12, 14, 16, 18, and 20; etoposide: 100 mg/m2 EV, days 2–4).

The overall response rate (ORR) and the complete responses after 2 cycles were 79% (90% CI, 65–89%) and 45%, respectively. Approximately half of the patients received an ASCT.

However, in those in the first line, the ORR was higher (86%), with CR of 69%. These responses were maintained in 90% of patients during follow-up. The OS at 1 year was 55% (95% CI, 38–69%). On the other hand, grade 4 neutropenia occurred in 92% of the cases [21, 22].

Another option for this high-risk group is the L-asparaginase, methotrexate, and dexamethasone (AspaMetDex) chemotherapy. In a phase 2 trial, it reported a CR rate of 61% after three cycles. Further results are needed to confirm the efficacy of this regimen [23].

In those patients with poor general condition and/or those who do not want to receive an ASCT, the management must be palliative or investigational since the prognosis is unfortunate.

However, there is evidence that the "sandwich" scheme of GELOX (gemcitabine, oxaliplatin, and L-asparaginase) and radiotherapy after at least two cycles of GELOX offers good results and acceptable toxicities in IE–IIE stages. The ORR was 96.3%, with CR of 74.1%. The OS and PFS at 2 years were both 86% [24, 25].

In relapse, if patients are tributary to treatment and have not received the SMILE scheme, this will become the second line based on the results described above. However, if the patient has been refractory to the SMILE scheme, the alternatives are also investigational and with scarce evidence.

There is a retrospective study with the GELOX scheme. The ORR was 40% (20% CR). Those who achieved CR (two received ASCT and maintenance with L-asparaginase) were disease free for 7 months [26].

Regarding ASCT and allogeneic stem cell transplantation (alloSCT), there is less evidence of its role in high risk and/or advanced stage ENKL.

There is a prospective study in the pre-L-asparaginase era which included 16 ENKL cases. Nine cases received an ASCT in first or second CR and the remaining in progression. The OS at 2 years was 71.3% (first to second CR) and 25.8%, respectively [27].

#### **Figure 1.**

*Proposed treatments for extranodal NK/T-cell lymphoma, nasal type NK/T. KPI, Korean prognostic index; RDT, radiotherapy; L-Asp, L-asparaginase; ASCT, autologous stem cell transplant; alloSCT, allogeneic stem cell transplant; R/R, relapsed/refractory.*

**47**

**3.2 Diagnosis**

**3.3 Staging and prognosis**

*Extranodal T/NK Lymphomas*

**3.1 General features**

prevents its development [32, 33].

*DOI: http://dx.doi.org/10.5772/intechopen.85541*

an alternative in very selected patients [28] (**Figure 1**).

II trials are missing to confirm these results [29–31].

general condition despite strictly following the diet.

nal T-cell lymphoma, and this will be further revised.

**3. Enteropathy-associated T-cell lymphoma (EATL)**

A registry study that includes 18 cases of patients who received an alloSCT demonstrated a PFS and OS at 5 years of 51 and 57%, respectively. Therefore, it becomes

New therapies, but not approved yet, are showing promising results. The most important results are those results obtained from the use of check point inhibitors (nivolumab and pembrolizumab). ORR oscillated between 57 and 100% but phase

The EATL currently refers exclusively to previous type I EATL and is clearly associated with celiac disease (CD) and occurs more frequently in patients of Northern European origin. Dermatitis herpetiformis and hyposplenism may be associated. Patients who are diagnosed at a higher age of celiac disease have a higher risk of having an LTAE and proper management with a gluten-free diet effectively

The most affected regions are the jejunum or ileum and are usually diagnosed after a resection for an acute abdomen. Patients have a rapid deterioration of their

Refractory celiac disease (RCD) is the precursor lesion. It is defined by histological changes associated with enteropathy in cases with strict diet for >12 months or severe and persistent symptoms that require a clinical intervention regardless of the duration of the strict diet. There is a sub-classification, RCD type I, if the intraepithelial lymphocytes show a normal phenotype and constitute a polyclonal population, and RCD type II, if the intraepithelial lymphocytes immunophenotype is aberrant and clonal products are detected on TCR gene rearrangement analysis [34]. Loss of heterozygosity at 9p21, involving CDKN2A/B locus, was detected in more than 50% of cases with EATL. Loss of 17p12-p13.2 (TP53) was reported in 23%, but a high frequency of aberrant nuclear p53 expression (75%) suggested alternate means of deregulation of this tumor suppressor. Surprisingly, there are more new findings in terms of etiology in the monomorphic epitheliotropic intesti-

Endoscopic findings show one or multiple ulcerated intestinal masses or large exophytic masses. At the serological level, tissue anti-transglutaminase IgA and antiendomysial IgA are the most sensitive and specific tests. The typing of HLA-DQ in search of the alleles that predispose to CD (DQ2/DQ8) is part of the diagnosis [35]. Histologically, EATL is characterized by a non-monomorphic infiltrate of cells

Staging will be carried out with the Lugano system [37] (see **Table 2**) Diagnostic tests include a CT scan, an endoscopic study, and a bone marrow biopsy. The index

with CD3 (+), CD7 (+), CD103 (+), cytotoxic proteins (+) CD8 (−/+), TCR-β (+/−), CD4 (−), CD5 (−), CD56 (−), and CD30 focally (+) in a subset of cases. Adjacent intraepithelial lymphocytes also have an aberrant immunophenotype CD3

(+), CD5 (−), CD8 (−), CD4 (−), and cytotoxic proteins (−). At the cytogenetic level, gains of 1q and 5q are observed [36].

#### *Extranodal T/NK Lymphomas DOI: http://dx.doi.org/10.5772/intechopen.85541*

A registry study that includes 18 cases of patients who received an alloSCT demonstrated a PFS and OS at 5 years of 51 and 57%, respectively. Therefore, it becomes an alternative in very selected patients [28] (**Figure 1**).

New therapies, but not approved yet, are showing promising results. The most important results are those results obtained from the use of check point inhibitors (nivolumab and pembrolizumab). ORR oscillated between 57 and 100% but phase II trials are missing to confirm these results [29–31].

## **3. Enteropathy-associated T-cell lymphoma (EATL)**

#### **3.1 General features**

*Peripheral T-cell Lymphomas*

2–4; methotrexate: 2000 mg/m2

occurred in 92% of the cases [21, 22].

are also investigational and with scarce evidence.

L-asparaginase) were disease free for 7 months [26].

evidence of its role in high risk and/or advanced stage ENKL.

L-asparaginase: 6000 U/m2

EV, days 2–4).

received an ASCT.

this regimen [23].

86% [24, 25].

respectively [27].

prognosis is unfortunate.

EV, day 1; ifosfamide: 1500 mg/m2

The overall response rate (ORR) and the complete responses after 2 cycles were 79% (90% CI, 65–89%) and 45%, respectively. Approximately half of the patients

Another option for this high-risk group is the L-asparaginase, methotrexate, and dexamethasone (AspaMetDex) chemotherapy. In a phase 2 trial, it reported a CR rate of 61% after three cycles. Further results are needed to confirm the efficacy of

In those patients with poor general condition and/or those who do not want to receive an ASCT, the management must be palliative or investigational since the

However, there is evidence that the "sandwich" scheme of GELOX (gemcitabine, oxaliplatin, and L-asparaginase) and radiotherapy after at least two cycles of GELOX offers good results and acceptable toxicities in IE–IIE stages. The ORR was 96.3%, with CR of 74.1%. The OS and PFS at 2 years were both

In relapse, if patients are tributary to treatment and have not received the SMILE

Regarding ASCT and allogeneic stem cell transplantation (alloSCT), there is less

There is a prospective study in the pre-L-asparaginase era which included 16 ENKL cases. Nine cases received an ASCT in first or second CR and the remaining in progression. The OS at 2 years was 71.3% (first to second CR) and 25.8%,

scheme, this will become the second line based on the results described above. However, if the patient has been refractory to the SMILE scheme, the alternatives

There is a retrospective study with the GELOX scheme. The ORR was 40% (20% CR). Those who achieved CR (two received ASCT and maintenance with

However, in those in the first line, the ORR was higher (86%), with CR of 69%. These responses were maintained in 90% of patients during follow-up. The OS at 1 year was 55% (95% CI, 38–69%). On the other hand, grade 4 neutropenia

EV, days 8, 10, 12, 14, 16, 18, and 20; etoposide: 100 mg/m2

EV, days 2–4; *E. coli*

**46**

**Figure 1.**

*cell transplant; R/R, relapsed/refractory.*

*Proposed treatments for extranodal NK/T-cell lymphoma, nasal type NK/T. KPI, Korean prognostic index; RDT, radiotherapy; L-Asp, L-asparaginase; ASCT, autologous stem cell transplant; alloSCT, allogeneic stem* 

The EATL currently refers exclusively to previous type I EATL and is clearly associated with celiac disease (CD) and occurs more frequently in patients of Northern European origin. Dermatitis herpetiformis and hyposplenism may be associated. Patients who are diagnosed at a higher age of celiac disease have a higher risk of having an LTAE and proper management with a gluten-free diet effectively prevents its development [32, 33].

The most affected regions are the jejunum or ileum and are usually diagnosed after a resection for an acute abdomen. Patients have a rapid deterioration of their general condition despite strictly following the diet.

Refractory celiac disease (RCD) is the precursor lesion. It is defined by histological changes associated with enteropathy in cases with strict diet for >12 months or severe and persistent symptoms that require a clinical intervention regardless of the duration of the strict diet. There is a sub-classification, RCD type I, if the intraepithelial lymphocytes show a normal phenotype and constitute a polyclonal population, and RCD type II, if the intraepithelial lymphocytes immunophenotype is aberrant and clonal products are detected on TCR gene rearrangement analysis [34].

Loss of heterozygosity at 9p21, involving CDKN2A/B locus, was detected in more than 50% of cases with EATL. Loss of 17p12-p13.2 (TP53) was reported in 23%, but a high frequency of aberrant nuclear p53 expression (75%) suggested alternate means of deregulation of this tumor suppressor. Surprisingly, there are more new findings in terms of etiology in the monomorphic epitheliotropic intestinal T-cell lymphoma, and this will be further revised.

### **3.2 Diagnosis**

Endoscopic findings show one or multiple ulcerated intestinal masses or large exophytic masses. At the serological level, tissue anti-transglutaminase IgA and antiendomysial IgA are the most sensitive and specific tests. The typing of HLA-DQ in search of the alleles that predispose to CD (DQ2/DQ8) is part of the diagnosis [35].

Histologically, EATL is characterized by a non-monomorphic infiltrate of cells with CD3 (+), CD7 (+), CD103 (+), cytotoxic proteins (+) CD8 (−/+), TCR-β (+/−), CD4 (−), CD5 (−), CD56 (−), and CD30 focally (+) in a subset of cases. Adjacent intraepithelial lymphocytes also have an aberrant immunophenotype CD3 (+), CD5 (−), CD8 (−), CD4 (−), and cytotoxic proteins (−).

At the cytogenetic level, gains of 1q and 5q are observed [36].

#### **3.3 Staging and prognosis**

Staging will be carried out with the Lugano system [37] (see **Table 2**) Diagnostic tests include a CT scan, an endoscopic study, and a bone marrow biopsy. The index


**Table 2.**

*Lugano staging system for gastrointestinal tract lymphoma.*

that best defined prognosis of the EATL is the prognostic index used for peripheral T lymphomas (IPI) [38].

#### **3.4 Treatment**

Because at the time of diagnosis the patient is usually in advanced stages and have a poor nutritional status, therapeutic success is scarce.

Surgery plays an important role in reducing tumor burden and decreasing perforations or bleeding during chemotherapy, but on the other hand, it can delay the onset of chemotherapy [39, 40].

The most used chemotherapy is the CHOP scheme. Only 50% of patients will be able to receive chemotherapy, and of these, only 50% will complete it. Of those who complete chemotherapy, 35–40% will achieve a complete remission of the lymphoma. The median duration of the response is approximately 6 months [41].

In those patients who are candidates to receive an ASCT in first remission, it is advisable to do it following the EBMT recommendations [42]. In the most recent study of the EBMT registry, 31 cases of patients with EATL were identified. With a median of 46 months of follow-up, the SLP and the OS at 4 years were 54–59%, respectively [43].

Refractory patients are unlikely to benefit from a second line of chemotherapy. No superiority of any regimen has been demonstrated, so it is advisable to follow usual schemes in the center of origin [44].

### **4. Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)**

#### **4.1 General features**

The MEITL is the intestinal lymphoma that was previously classified as EATL type II. Because it has shown both clinical and biological differences with the EATL, it has been constituted as a new entity. It is not associated with celiac disease and has a greater incidence in Asian and Hispanic populations. Its frequency is 10–15% of intestinal T lymphomas.

**49**

*Extranodal T/NK Lymphomas*

**4.2 Diagnosis**

**4.3 Treatment**

(CR 38%)[46].

for T-cell neoplasia [42, 49].

disease and arthritis [51, 52].

isochromosome 7q and trisomy 8 [53].

**5.1 General features**

prognosis [50].

**5.2 Diagnosis**

*DOI: http://dx.doi.org/10.5772/intechopen.85541*

CD3 (+), CD8 (+), CD56 (+), TCR-β (+), CD4 (−).

lial lymphocytes show an aberrant immunophenotype.

tivity for the megakaryocyte-associated tyrosine kinase (MATK).

asparaginase to EPOCH regimen in a non-responding patient [48].

**5. Hepatosplenic T-cell lymphoma (HSTL)**

The tumor is composed of a monomorphic infiltrate. The immunophenotype is

In exceptional cases, TCR-γδ (+) has been demonstrated. Adjacent intraepithe-

One way to differentiate it from other NK/T and EATL lymphomas is the posi-

At the cytogenetic level, gains are observed in MYC (locus 8q24) [45]. The *staging and prognosis* will be carried out in the same way as for the EATL.

There are no clinical trials that allow favoring one treatment regimen over another. However, there are retrospective studies where it is confirmed that the anthracycline regimens are the most used (72%). The overall response rate was 46%

Recently, the potential effect of pralatrexate has been reported in a relapsed patient after anthracycline containing regimen [47] and also the addition of PEG-

The recommendations to perform an autologous transplant in the first remission are the same as in the EATL following the EBMT experience and recommendation

HSTL is a rare entity. It represents 1% of non-Hodgkin's lymphoma and 3% of T-lymphoma. Survival at 5 years does not exceed 7%; therefore, it has a poor clinical

The etiology is unclear; however, it is postulated that chronic stimulation in patients with immune deficiencies or immune dysregulation could be important. Twenty percent of cases occur in young patients with some degree of immunosuppression (posttransplant, under treatment of leukemia). It has also been associated with the use of TNFα and immunomodulators in patients with inflammatory bowel

It is characterized by the proliferation of malignant T cells of medium size in the hepatic sinusoids, in the red pulp of the spleen, and in the bone marrow. The immunophenotype of the tumor cell is CD4−, CD8− (CD8+ alginates), CD2+, CD3+, CD42, CD52, CD76, and CD82. The TCR is usually gamma-delta, although there are cases described alpha-beta. The detected cytogenetic anomalies include

Recently, the genetic basis of HSTL was described using whole exome sequencing. Some chromatin-modifying genes (INO80, SETD2, and ARID1B) were commonly mutated in HSTL; there are frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%) and less frequent events in EZH2, KRAS, and TP53. SETD2 that works as a tumor suppressor gene was the most frequently silenced gene [54]. To further determine the pathogenesis, a multicenter group performed an array-based

## **4.2 Diagnosis**

*Peripheral T-cell Lymphomas*

T lymphomas (IPI) [38].

the onset of chemotherapy [39, 40].

using both a subscript (1 or 2) and E, e.g., II1Epancreas.

*Lugano staging system for gastrointestinal tract lymphoma.*

usual schemes in the center of origin [44].

**4.1 General features**

of intestinal T lymphomas.

**3.4 Treatment**

**Table 2.**

that best defined prognosis of the EATL is the prognostic index used for peripheral

Stage I Tumor confined to GI tract. Single primary site or multiple, noncontiguous lesions.

from primary GI site.

Stage IIE Penetration of serosa to involve adjacent organs or tissues

Where there is both nodal involvement and penetration to involve adjacent organs, stage should be denoted

Stage IV Disseminated extranodal involvement, or, a GI tract lesion with

supra-diaphragmatic nodal involvement.

intestine).

Nodal involvement II1 local (paragastric in cases of gastric lymphoma and para-intestinal for intestinal

II2 distant (mesenteric in the case of an intestinal primary, otherwise; para-aortic paracaval, pelvic, inguinal).

lymphoma)

(enumerate actual site of involvement, e.g., IIEpancreas, IIElarge

Stage II Tumor extending into abdomen

Because at the time of diagnosis the patient is usually in advanced stages and

The most used chemotherapy is the CHOP scheme. Only 50% of patients will be able to receive chemotherapy, and of these, only 50% will complete it. Of those who complete chemotherapy, 35–40% will achieve a complete remission of the lymphoma. The median duration of the response is approximately 6 months [41]. In those patients who are candidates to receive an ASCT in first remission, it is advisable to do it following the EBMT recommendations [42]. In the most recent study of the EBMT registry, 31 cases of patients with EATL were identified. With a median of 46 months of follow-up, the SLP and the OS at 4 years were 54–59%, respectively [43]. Refractory patients are unlikely to benefit from a second line of chemotherapy. No superiority of any regimen has been demonstrated, so it is advisable to follow

Surgery plays an important role in reducing tumor burden and decreasing perforations or bleeding during chemotherapy, but on the other hand, it can delay

**4. Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)**

The MEITL is the intestinal lymphoma that was previously classified as EATL type II. Because it has shown both clinical and biological differences with the EATL, it has been constituted as a new entity. It is not associated with celiac disease and has a greater incidence in Asian and Hispanic populations. Its frequency is 10–15%

have a poor nutritional status, therapeutic success is scarce.

**48**

The tumor is composed of a monomorphic infiltrate. The immunophenotype is CD3 (+), CD8 (+), CD56 (+), TCR-β (+), CD4 (−).

In exceptional cases, TCR-γδ (+) has been demonstrated. Adjacent intraepithelial lymphocytes show an aberrant immunophenotype.

One way to differentiate it from other NK/T and EATL lymphomas is the positivity for the megakaryocyte-associated tyrosine kinase (MATK).

At the cytogenetic level, gains are observed in MYC (locus 8q24) [45]. The *staging and prognosis* will be carried out in the same way as for the EATL.

## **4.3 Treatment**

There are no clinical trials that allow favoring one treatment regimen over another. However, there are retrospective studies where it is confirmed that the anthracycline regimens are the most used (72%). The overall response rate was 46% (CR 38%)[46].

Recently, the potential effect of pralatrexate has been reported in a relapsed patient after anthracycline containing regimen [47] and also the addition of PEGasparaginase to EPOCH regimen in a non-responding patient [48].

The recommendations to perform an autologous transplant in the first remission are the same as in the EATL following the EBMT experience and recommendation for T-cell neoplasia [42, 49].

## **5. Hepatosplenic T-cell lymphoma (HSTL)**

### **5.1 General features**

HSTL is a rare entity. It represents 1% of non-Hodgkin's lymphoma and 3% of T-lymphoma. Survival at 5 years does not exceed 7%; therefore, it has a poor clinical prognosis [50].

The etiology is unclear; however, it is postulated that chronic stimulation in patients with immune deficiencies or immune dysregulation could be important. Twenty percent of cases occur in young patients with some degree of immunosuppression (posttransplant, under treatment of leukemia). It has also been associated with the use of TNFα and immunomodulators in patients with inflammatory bowel disease and arthritis [51, 52].

## **5.2 Diagnosis**

It is characterized by the proliferation of malignant T cells of medium size in the hepatic sinusoids, in the red pulp of the spleen, and in the bone marrow. The immunophenotype of the tumor cell is CD4−, CD8− (CD8+ alginates), CD2+, CD3+, CD42, CD52, CD76, and CD82. The TCR is usually gamma-delta, although there are cases described alpha-beta. The detected cytogenetic anomalies include isochromosome 7q and trisomy 8 [53].

Recently, the genetic basis of HSTL was described using whole exome sequencing. Some chromatin-modifying genes (INO80, SETD2, and ARID1B) were commonly mutated in HSTL; there are frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%) and less frequent events in EZH2, KRAS, and TP53. SETD2 that works as a tumor suppressor gene was the most frequently silenced gene [54]. To further determine the pathogenesis, a multicenter group performed an array-based

DNA methylation profiling and identified eight genes consistently hypermethylated (BCL11B, CXCR6, CD5, GIMAP7, SEPT9, LTA, UBAC2, and UXS1) and four genes hypomethylated (ADARB1, NR1H3, NFIC, and ST3GAL3) [55].

## **5.3 Staging and prognosis**

Staging is performed with the Ann Arbor system. A specific prognostic index for this lymphoma has not been described because of its low frequency.

## **5.4 Treatment**

The most used treatments are CHOP and hyper-CVAD. The cases that respond can go directly to autologous or allogeneic transplant.

Other regimens described in a retrospective study (*n* = 14) have been ICE and IVAC in first line and also in rescue after CHOP. While it is a small series, the authors emphasize that the use of more intensive schemes followed by precursor transplant hematopoietic agents could improve efficacy data [56].

The relapse-free time and the OS post alloSCT are 18 and 68 months, respectively. The relapse-free time and the OS at 3 years are 42 and 56%, respectively. In this way, it is the only treatment that offers some probability of healing [57].

## **Author details**

Silvana Novelli1,2

1 Hematology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute (IIB Sant-Pau), Autonomous University of Barcelona, Spain

2 José Carreras Leukemia Research Institute, Autonomous University of Barcelona, Spain

\*Address all correspondence to: snovelli@santpau.cat

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**51**

*Extranodal T/NK Lymphomas*

[1] Swerdlow SH. World Health

**References**

on Cancer; 2017

*DOI: http://dx.doi.org/10.5772/intechopen.85541*

Organization; International Agency for Research on Cancer. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th edition. Lyon: International Agency for Research

lymphoma, nasal type: A multicentre,

[10] Guan H, Huang Y, Wen W, Xu M, Zan Q, Zhang Z. Primary central nervous system extranodal NK/T-cell lymphoma, nasal type: Case report and review of the literature. Journal of Neuro-Oncology. 2011;**103**(2):387-391

[11] Barrington SF et al. Role of imaging in the staging and response assessment of lymphoma: Consensus of the

International Conference on Malignant

[12] Yan Z et al. A TNM staging system for nasal NK/T-cell lymphoma. PLoS

[13] Lee J et al. Extranodal natural killer T-cell lymphoma, nasal-type: A prognostic model from a retrospective multicenter study. Journal of Clinical Oncology. 2006;**24**(4):612-618

[14] Au W, Pang A, Choy C, Chim C, Kwong Y, Dc W. Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood. 2004;**104**(1):243-249

[15] Suzuki R et al. Prospective measurement of Epstein-Barr virus-DNA in plasma and peripheral blood mononuclear cells of extranodal NK/Tcell lymphoma, nasal type. Blood. Dec 1

[16] Yang Y et al. Risk-adapted therapy for early-stage extranodal nasaltype NK/T-cell lymphoma: analysis from a multicenter study Blood.

[17] Juan Huang M et al. Early or up-front radiotherapy improved

2011;**118**(23):6018-6022

2015;**126**:1424-1432

Lymphomas imaging Working Group. Journal of Clinical Oncology.

2014;**32**(27):3048-3058

One. 2015;**10**(6):1-17

retrospective analysis. Lancet Haematology. 2015;**2**(2):e66-e74

[2] Au W et al. ENKL nasal or ex-nasal.

International analysis of the frequency and outcomes of NK/T-cell lymphomas. Best Practice & Research. Clinical Haematology. 2013;**26**(1):23-32

[4] Harabuchi Y, Yamanaka N, Kataura A, Imai S, Kinoshita T, Osato T. Epstein-Barr virus in nasal T-cell lymphomas in patients with lethal midline granuloma.

Lancet. 1990;**335**(8682):128-130

reticulosis/midline malignant reticulosis) in Western China. The Journal of Pathology. 1994;**173**(2):81-87

1994;**18**(9):938-946

[5] Van Gorp J et al. Epstein-Barr virus in nasal T-cell lymphomas (polymorphic

[6] Chan JK et al. Detection of Epstein-Barr viral RNA in malignant lymphomas of the upper aerodigestive tract. The American Journal of Surgical Pathology.

[7] Medeiros LJ, Miranda RN. Diagnostic Pathology. Lymph Nodes Extranodal Lymphomas. Second edition. Philadelphia, PA: Elsevier; 2018

[8] Yamaguchi M, Oguchi M, Suzuki R. Extranodal NK/T-cell lymphoma: Updates in biology and management strategies. Best Practice & Research. Clinical Haematology. 2018;**31**(3):315-321

[9] Kim SJ et al. Risk stratification on the basis of Deauville score on PET-CT and the presence of Epstein-Barr virus DNA after completion of primary treatment for extranodal natural killer/T-cell

Blood. 2016;**113**(17):3931-3938

[3] William BM, Armitage JO.

## **References**

*Peripheral T-cell Lymphomas*

**5.3 Staging and prognosis**

**5.4 Treatment**

**Author details**

Silvana Novelli1,2

**50**

Spain

provided the original work is properly cited.

\*Address all correspondence to: snovelli@santpau.cat

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 José Carreras Leukemia Research Institute, Autonomous University of Barcelona,

1 Hematology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute (IIB Sant-Pau), Autonomous University of Barcelona, Spain

DNA methylation profiling and identified eight genes consistently hypermethylated (BCL11B, CXCR6, CD5, GIMAP7, SEPT9, LTA, UBAC2, and UXS1) and four genes

Staging is performed with the Ann Arbor system. A specific prognostic index for

The most used treatments are CHOP and hyper-CVAD. The cases that respond

Other regimens described in a retrospective study (*n* = 14) have been ICE and IVAC in first line and also in rescue after CHOP. While it is a small series, the authors emphasize that the use of more intensive schemes followed by precursor

The relapse-free time and the OS post alloSCT are 18 and 68 months, respectively. The relapse-free time and the OS at 3 years are 42 and 56%, respectively. In this way, it is the only treatment that offers some probability of healing [57].

hypomethylated (ADARB1, NR1H3, NFIC, and ST3GAL3) [55].

this lymphoma has not been described because of its low frequency.

transplant hematopoietic agents could improve efficacy data [56].

can go directly to autologous or allogeneic transplant.

[1] Swerdlow SH. World Health Organization; International Agency for Research on Cancer. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th edition. Lyon: International Agency for Research on Cancer; 2017

[2] Au W et al. ENKL nasal or ex-nasal. Blood. 2016;**113**(17):3931-3938

[3] William BM, Armitage JO. International analysis of the frequency and outcomes of NK/T-cell lymphomas. Best Practice & Research. Clinical Haematology. 2013;**26**(1):23-32

[4] Harabuchi Y, Yamanaka N, Kataura A, Imai S, Kinoshita T, Osato T. Epstein-Barr virus in nasal T-cell lymphomas in patients with lethal midline granuloma. Lancet. 1990;**335**(8682):128-130

[5] Van Gorp J et al. Epstein-Barr virus in nasal T-cell lymphomas (polymorphic reticulosis/midline malignant reticulosis) in Western China. The Journal of Pathology. 1994;**173**(2):81-87

[6] Chan JK et al. Detection of Epstein-Barr viral RNA in malignant lymphomas of the upper aerodigestive tract. The American Journal of Surgical Pathology. 1994;**18**(9):938-946

[7] Medeiros LJ, Miranda RN. Diagnostic Pathology. Lymph Nodes Extranodal Lymphomas. Second edition. Philadelphia, PA: Elsevier; 2018

[8] Yamaguchi M, Oguchi M, Suzuki R. Extranodal NK/T-cell lymphoma: Updates in biology and management strategies. Best Practice & Research. Clinical Haematology. 2018;**31**(3):315-321

[9] Kim SJ et al. Risk stratification on the basis of Deauville score on PET-CT and the presence of Epstein-Barr virus DNA after completion of primary treatment for extranodal natural killer/T-cell

lymphoma, nasal type: A multicentre, retrospective analysis. Lancet Haematology. 2015;**2**(2):e66-e74

[10] Guan H, Huang Y, Wen W, Xu M, Zan Q, Zhang Z. Primary central nervous system extranodal NK/T-cell lymphoma, nasal type: Case report and review of the literature. Journal of Neuro-Oncology. 2011;**103**(2):387-391

[11] Barrington SF et al. Role of imaging in the staging and response assessment of lymphoma: Consensus of the International Conference on Malignant Lymphomas imaging Working Group. Journal of Clinical Oncology. 2014;**32**(27):3048-3058

[12] Yan Z et al. A TNM staging system for nasal NK/T-cell lymphoma. PLoS One. 2015;**10**(6):1-17

[13] Lee J et al. Extranodal natural killer T-cell lymphoma, nasal-type: A prognostic model from a retrospective multicenter study. Journal of Clinical Oncology. 2006;**24**(4):612-618

[14] Au W, Pang A, Choy C, Chim C, Kwong Y, Dc W. Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood. 2004;**104**(1):243-249

[15] Suzuki R et al. Prospective measurement of Epstein-Barr virus-DNA in plasma and peripheral blood mononuclear cells of extranodal NK/Tcell lymphoma, nasal type. Blood. Dec 1 2011;**118**(23):6018-6022

[16] Yang Y et al. Risk-adapted therapy for early-stage extranodal nasaltype NK/T-cell lymphoma: analysis from a multicenter study Blood. 2015;**126**:1424-1432

[17] Juan Huang M et al. Early or up-front radiotherapy improved

#### *Peripheral T-cell Lymphomas*

survival of localized extranodal NK/Tcell lymphoma, nasal-type in the upper aerodigestive tract. International Journal of Radiation Oncology, Biology, Physics. 2008;**70**(1):166-174

[18] Yamaguchi M et al. Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/Tcell lymphoma: Japan Clinical Oncology Group Study JCOG0211. Journal of Clinical Oncology. 2009;**27**(33):5594-5600

[19] Kim SJ et al. Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-cell lymphoma: Consortium for improving survival of lymphoma study. Journal of Clinical Oncology. 2009;**27**(35):6027-6032

[20] Dong L-H et al. Sequential DICE combined with L-asparaginase chemotherapy followed by involved field radiation in newly diagnosed, stage IE to IIE, nasal and extranodal NK/T-cell lymphoma. Leukemia & Lymphoma. 2016;**57**(7):1600-1606

[21] Yamaguchi M et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: The NK-cell tumor study group study. Journal of Clinical Oncology. 2011;**29**(33):4410-4416

[22] Kwong Y et al. SMILE for natural killer/T-cell lymphoma: Analysis of safety and efficacy from the Asia Lymphoma Study Group. Blood. 2012;**120**(15):2973-2981

[23] Jaccard A et al. Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood. 2011;**117**(6):1834-1839

[24] Wang L et al. First-line combination of gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE extranodal natural killer/T-cell lymphoma. Cancer. 2013;**119**(2):348-355

[25] Wang H et al. Comparison of gemcitabine, oxaliplatin and L-asparaginase and etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone as first-line chemotherapy in patients with stage IE to IIE extranodal natural killer/T-cell lymphoma: A multicenter retrospective study. Leukemia & Lymphoma. 2015;**56**(4):971-977

[26] Ahn HK et al. Gemcitabine alone and/or containing chemotherapy is efficient in refractory or relapsed NK/Tcell lymphoma. Investigational New Drugs. 2013;**31**(2):469-472

[27] Kim HJ et al. High-dose chemotherapy with autologous stem cell transplantation in extranodal NK/T-cell lymphoma: A retrospective comparison with non-transplantation cases. Bone Marrow Transplantation. 2006;**37**(9):819-824

[28] Tse E et al. Allogeneic haematopoietic SCT for natural killer/T-cell lymphoma: A multicentre analysis from the Asia Lymphoma Study Group. Bone Marrow Transplantation. 2014;**49**(7):902-906

[29] Lai J, Xu P, Jiang X, Zhou S, Liu A. Successful treatment with antiprogrammed-death-1 antibody in a relapsed natural killer/T-cell lymphoma patient with multi-line resistance: A case report. BMC Cancer. 2017;**17**(1):507

[30] Li X et al. Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. Journal of Hematology & Oncology. 2018;**11**(1):15

**53**

*Extranodal T/NK Lymphomas*

2018;**97**(1):193-196

2008;**53**(4):972-976

2018;**13**(4):308-317

2015;**27**(5):343-352

*DOI: http://dx.doi.org/10.5772/intechopen.85541*

[40] Novakovic BJ, Novakovic S,

Frkovic-Grazio S. A single-center report on clinical features and treatment response in patients with intestinal T cell non-Hodgkin's lymphomas. Oncology Reports. 2006;**16**(1):191-195

[41] Di Sabatino A, Biagi F, Gobbi PG, Corazza GR. How I treat enteropathyassociated T-cell lymphoma. Blood.

[42] Sureda A et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: Current practice in Europe. Bone Marrow Transplantation. 2015;**50**(8):1037-1056, 2015

[43] Jantunen E et al. Autologous stem cell transplantation in adult patients with peripheral T-cell lymphoma: A nation-wide survey. Bone Marrow Transplantation. 2004;**33**(4):405-410

[44] Raderer M et al. Second line chemotherapy in patients with enteropathy-associated T cell lymphoma: A retrospective single center analysis. Annals of Hematology.

[45] Chen Y, Tan S-Y, Petersson BF, Khor YM, Gopalakrishnan SK, Tan D. Occult recurrence of monomorphic epitheliotropic intestinal T-cell

lymphoma and the role of MATK gene expression in diagnosis. Hematological

[46] Tse E et al. Type II enteropathyassociated T-cell lymphoma: A multicenter analysis from the Asia Lymphoma Study Group. American Journal of Hematology.

[47] Tabata R, Tabata C, Okamura M, Takei Y, Ohshima K. Successful treatment of monomorphic epitheliotropic intestinal T cell

lymphoma with pralatrexate. Annals of Hematology. May 2019;**98**(5):1301-1303

Oncology. 2017;**35**(4):852-855

2012;**87**(7):663-668

2012;**91**(1):57-61

2012;**119**(11):2458-2468

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[32] Silano M et al. Effect of a glutenfree diet on the risk of enteropathyassociated T-cell lymphoma in celiac disease. Digestive Diseases and Sciences.

[33] Lebwohl B et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: A population-based cohort study. Annals of Internal Medicine. 2013;**159**(3):169-175

[34] Chander U, Leeman-Neill RJ, Bhagat G. Pathogenesis of enteropathyassociated t cell lymphoma. Current Hematologic Malignancy Reports.

[35] Stamnaes J, Sollid LM. Celiac disease: Autoimmunity in response to food antigen. Seminars in Immunology.

[36] deLeeuw RJ et al. Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology. 2007;**132**(5):1902-1911

[37] Rohatiner A et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Annals of Oncology. 1994;**5**(5):397-400

[38] Delabie J et al. Enteropathyassociated T-cell lymphoma: Clinical and histological findings from the international peripheral T-cell lymphoma project. Blood.

[39] Nijeboer P et al. Treatment response in enteropathy associated T-cell lymphoma; survival in a large multicenter cohort. American Journal of

Hematology. 2015;**90**(6):493-498

2011;**118**(1):148-155

[31] Chan TSY, Li J, Loong F, Khong P-L, Tse E, Kwong Y-L. PD1

#### *Extranodal T/NK Lymphomas DOI: http://dx.doi.org/10.5772/intechopen.85541*

blockade with low-dose nivolumab in NK/T cell lymphoma failing L-asparaginase: Efficacy and safety. Annals of Hematology. 2018;**97**(1):193-196

*Peripheral T-cell Lymphomas*

Physics. 2008;**70**(1):166-174

[19] Kim SJ et al. Phase II trial of

concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-cell lymphoma: Consortium for improving survival of lymphoma study. Journal of Clinical Oncology. 2009;**27**(35):6027-6032

[20] Dong L-H et al. Sequential DICE combined with L-asparaginase chemotherapy followed by involved field radiation in newly diagnosed, stage IE to IIE, nasal and extranodal NK/T-cell lymphoma. Leukemia & Lymphoma. 2016;**57**(7):1600-1606

[21] Yamaguchi M et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: The NK-cell tumor study group study. Journal of Clinical Oncology.

[22] Kwong Y et al. SMILE for natural killer/T-cell lymphoma: Analysis of safety and efficacy from the Asia Lymphoma Study Group. Blood.

2011;**29**(33):4410-4416

2012;**120**(15):2973-2981

2011;**117**(6):1834-1839

[23] Jaccard A et al. Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood.

survival of localized extranodal NK/Tcell lymphoma, nasal-type in the upper aerodigestive tract. International Journal of Radiation Oncology, Biology, [24] Wang L et al. First-line combination

of gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE extranodal natural killer/T-cell lymphoma. Cancer.

[25] Wang H et al. Comparison of gemcitabine, oxaliplatin and L-asparaginase and etoposide, vincristine, doxorubicin,

cyclophosphamide and prednisone as first-line chemotherapy in patients with stage IE to IIE extranodal natural killer/T-cell lymphoma: A multicenter retrospective study. Leukemia & Lymphoma. 2015;**56**(4):971-977

[26] Ahn HK et al. Gemcitabine alone and/or containing chemotherapy is efficient in refractory or relapsed NK/Tcell lymphoma. Investigational New

chemotherapy with autologous stem cell transplantation in extranodal NK/T-cell lymphoma: A retrospective comparison with non-transplantation cases. Bone Marrow Transplantation.

[29] Lai J, Xu P, Jiang X, Zhou S, Liu A. Successful treatment with antiprogrammed-death-1 antibody in a relapsed natural killer/T-cell lymphoma patient with multi-line resistance: A case report. BMC Cancer. 2017;**17**(1):507

pembrolizumab in relapsed/refractory NK/T-cell lymphoma. Journal of Hematology & Oncology. 2018;**11**(1):15

Drugs. 2013;**31**(2):469-472

[27] Kim HJ et al. High-dose

2006;**37**(9):819-824

2014;**49**(7):902-906

[30] Li X et al. Activity of

[31] Chan TSY, Li J, Loong F, Khong P-L, Tse E, Kwong Y-L. PD1

[28] Tse E et al. Allogeneic haematopoietic SCT for natural killer/T-cell lymphoma: A multicentre analysis from the Asia Lymphoma Study Group. Bone Marrow Transplantation.

2013;**119**(2):348-355

[18] Yamaguchi M et al. Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/Tcell lymphoma: Japan Clinical Oncology Group Study JCOG0211. Journal of Clinical Oncology. 2009;**27**(33):5594-5600

**52**

[32] Silano M et al. Effect of a glutenfree diet on the risk of enteropathyassociated T-cell lymphoma in celiac disease. Digestive Diseases and Sciences. 2008;**53**(4):972-976

[33] Lebwohl B et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: A population-based cohort study. Annals of Internal Medicine. 2013;**159**(3):169-175

[34] Chander U, Leeman-Neill RJ, Bhagat G. Pathogenesis of enteropathyassociated t cell lymphoma. Current Hematologic Malignancy Reports. 2018;**13**(4):308-317

[35] Stamnaes J, Sollid LM. Celiac disease: Autoimmunity in response to food antigen. Seminars in Immunology. 2015;**27**(5):343-352

[36] deLeeuw RJ et al. Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology. 2007;**132**(5):1902-1911

[37] Rohatiner A et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Annals of Oncology. 1994;**5**(5):397-400

[38] Delabie J et al. Enteropathyassociated T-cell lymphoma: Clinical and histological findings from the international peripheral T-cell lymphoma project. Blood. 2011;**118**(1):148-155

[39] Nijeboer P et al. Treatment response in enteropathy associated T-cell lymphoma; survival in a large multicenter cohort. American Journal of Hematology. 2015;**90**(6):493-498

[40] Novakovic BJ, Novakovic S, Frkovic-Grazio S. A single-center report on clinical features and treatment response in patients with intestinal T cell non-Hodgkin's lymphomas. Oncology Reports. 2006;**16**(1):191-195

[41] Di Sabatino A, Biagi F, Gobbi PG, Corazza GR. How I treat enteropathyassociated T-cell lymphoma. Blood. 2012;**119**(11):2458-2468

[42] Sureda A et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: Current practice in Europe. Bone Marrow Transplantation. 2015;**50**(8):1037-1056, 2015

[43] Jantunen E et al. Autologous stem cell transplantation in adult patients with peripheral T-cell lymphoma: A nation-wide survey. Bone Marrow Transplantation. 2004;**33**(4):405-410

[44] Raderer M et al. Second line chemotherapy in patients with enteropathy-associated T cell lymphoma: A retrospective single center analysis. Annals of Hematology. 2012;**91**(1):57-61

[45] Chen Y, Tan S-Y, Petersson BF, Khor YM, Gopalakrishnan SK, Tan D. Occult recurrence of monomorphic epitheliotropic intestinal T-cell lymphoma and the role of MATK gene expression in diagnosis. Hematological Oncology. 2017;**35**(4):852-855

[46] Tse E et al. Type II enteropathyassociated T-cell lymphoma: A multicenter analysis from the Asia Lymphoma Study Group. American Journal of Hematology. 2012;**87**(7):663-668

[47] Tabata R, Tabata C, Okamura M, Takei Y, Ohshima K. Successful treatment of monomorphic epitheliotropic intestinal T cell lymphoma with pralatrexate. Annals of Hematology. May 2019;**98**(5):1301-1303 [48] Gentille C, Qin Q, Barbieri A, Ravi PS, Iyer S. Use of PEG-asparaginase in monomorphic epitheliotropic intestinal T-cell lymphoma, a disease with diagnostic and therapeutic challenges. ecancermedicalscience. 2017;**11**:771

[49] Jantunen E, Boumendil A, Finel H. Autologous stem cell transplantation for enteropathy-associated T-cell lymphoma: A retrospective study by the EBMT. Blood. 2013;**121**(13):2529-2532

[50] Vose JM, Neumann M, Harris ME. International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcomes international T-cell lymphoma project. Journal of Clinical Oncology. 2008;**26**(25):4124-4130

[51] Weidmann E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990. Leukemia. 2000;**14**(6):991-997

[52] Parakkal D, Sifuentes H, Semer R, Ehrenpreis ED. Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: Expanding the groups at risk. European Journal of Gastroenterology & Hepatology. 2011;**23**(12):1150-1156

[53] Calvaruso M et al. Challenges and new prospects in hepatosplenic γδ T-cell lymphoma. Leukemia & Lymphoma. 2014;**55**:1-9

[54] McKinney M et al. The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discovery. 2017;**7**(4):369-379

[55] Bergmann AK et al. DNA methylation profiling identifies candidate genes for the pathogenesis of hepatosplenic T-cell lymphoma. Haematologica. 2018;**2018**:196196

[56] Voss MH et al. Intensive induction chemotherapy followed by early highdose therapy and hematopoietic stem

cell transplantation results in improved outcome for patients with hepatosplenic T-cell lymphoma: A single institution experience. Clinical Lymphoma, Myeloma & Leukemia. 2013;**13**(1):8-14

[57] Rashidi A, Cashen AF. Outcomes of allogeneic stem cell transplantation in hepatosplenic T-cell lymphoma. Blood Cancer Journal. 2015;**5**:e318

**55**

**Chapter 5**

**Abstract**

**1. Introduction**

An Overview

*and Jen Chin Wang*

*Preethi Ramachandran, Alok Aggarwal*

options of these rare but clinically important entities.

T-cell receptor, hepatosplenic T cell lymphoma

for only <1% of lymphoid tumors [2].

**Keywords:** gamma-delta T-cell, T cell lymphoma, non-Hodgkin lymphoma,

T/NK (natural killer) cell lymphomas are uncommon lymphomas accounting for about 6% of all non-Hodgkin lymphoma (NHL). B-cell lymphomas account for the majority being 80% and Hodgkin lymphoma accounts for 7% of NHLs in the United States according to the Surveillance, Epidemiology, and End Results program (SEER) over a 10-year period from 1997 till 2006 [1]. According to the updated 2016 revision of World Health Organization Classification (WHO) of T-cell lymphoid neoplasms, there are about 27 types of mature T and NK cell neoplasms. Amongst all types, gamma-delta T-cell lymphoma (γδ-TCL) accounts

T lymphocytes recognize antigens through T-cell receptors (TCRs). TCRs are polypeptide heterodimers which mostly constitutes α and β chains and rarely γ and δ chains. Alpha-beta T cells (Tαβ) constitute 95% of all T cells while gamma-delta T cells (Tγδ) make up only a small proportion accounting to <5% of all circulating lymphocytes. Majority of lymphoid tissues are made of αβ T cells than γδ subtype. Gammadelta (γδ) subtype shows selective tropism for the red pulp of the spleen, mucosal tissues, gastrointestinal epithelial tissues, skin and rarely lymphoid tissue. Hence the

Gamma-Delta T-cell Lymphoma:

Gamma-delta T-cell lymphomas are very rare and aggressive T-cell neoplasms with complex heterogenicity and diagnostic complexity. Gamma-delta T lymphocytes originate from CD4− CD8− (double negative) thymocytes in the bone marrow and are distinct from alpha beta subtype. Four entities of gamma-delta lymphomas recognized by 2016 WHO classification of lymphoid neoplasms include: hepatosplenic Tγδ lymphoma (HSγδTL), primary cutaneous gamma-delta TCL (PCTCL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) and large granular lymphocytic leukemias (T-LGL). Extensive literature search based on small case series and case reports identifies few more subtypes of gamma-delta T-lymphomas which were not previously classified by World Health Organization. There remains a critical gap in our understanding of the subtypes of gamma-delta T-cell lymphomas and a lack of updated summarization. In this review, we summarize in detail on the classification, biology, heterogenicity, diagnosis, clinical behavior and treatment

## **Chapter 5**

*Peripheral T-cell Lymphomas*

[48] Gentille C, Qin Q, Barbieri A, Ravi PS, Iyer S. Use of PEG-asparaginase

in monomorphic epitheliotropic

intestinal T-cell lymphoma, a disease with diagnostic and therapeutic challenges. ecancermedicalscience. 2017;**11**:771

cell transplantation results in improved outcome for patients with hepatosplenic T-cell lymphoma: A single institution experience. Clinical Lymphoma, Myeloma & Leukemia. 2013;**13**(1):8-14

[57] Rashidi A, Cashen AF. Outcomes of allogeneic stem cell transplantation in hepatosplenic T-cell lymphoma. Blood

Cancer Journal. 2015;**5**:e318

[49] Jantunen E, Boumendil A, Finel H. Autologous stem cell transplantation for enteropathy-associated T-cell lymphoma: A retrospective study by the EBMT. Blood. 2013;**121**(13):2529-2532

[50] Vose JM, Neumann M, Harris ME. International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical

outcomes international T-cell lymphoma project. Journal of Clinical Oncology.

[51] Weidmann E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990.

[52] Parakkal D, Sifuentes H, Semer R, Ehrenpreis ED. Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: Expanding the groups at risk. European Journal of Gastroenterology & Hepatology.

[53] Calvaruso M et al. Challenges and new prospects in hepatosplenic γδ T-cell lymphoma. Leukemia & Lymphoma.

[54] McKinney M et al. The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discovery. 2017;**7**(4):369-379

[56] Voss MH et al. Intensive induction chemotherapy followed by early highdose therapy and hematopoietic stem

[55] Bergmann AK et al. DNA methylation profiling identifies candidate genes for the pathogenesis of hepatosplenic T-cell lymphoma. Haematologica. 2018;**2018**:196196

Leukemia. 2000;**14**(6):991-997

2008;**26**(25):4124-4130

2011;**23**(12):1150-1156

2014;**55**:1-9

**54**
