103 Mature T-Cell and Natural Killer Cell Lymphomas

Question 1

Whereas B-cell lymphomas are often characterized by a specific immunophenotypic profile, T-cell lymphomas are often characterized by

Answer 1

Antigen aberrancy

In establishing the diagnosis of T-cell NHL, it is important to exclude a reactive process

Question 2

Serologic testing for this virus is particularly important in establishing a new diagnosis of PTCL in a person from an endemic area

INITITAL WORKUP

In addition to physical examination, initial evaluation should include systemic imaging (preferably positron emission tomography with computed tomography [PET-CT] or CT of the chest, abdomen, and pelvis), marrow aspirate or biopsy, and laboratory evaluation

Answer 2

Human T-cell lymphotrophic virus (HTLV)-1

Because adult T-cell leukemia/lymphoma (ATL) represents approximately 9% of PTCL in such areas, is associated with a different prognosis, and usually requires alternative therapy.

Question 3

Prognostic index for T-cell lymphoma (PIT) includes

Answer 3

Age, performance status, LDH level, and marrow involvement

Question 4

IPTCLP score

Answer 4

Albumin, performance status, stage, and absolute neutrophil count

Question 5

Most commonly used backbone for initial therapy of patients with PTCL

Answer 5

CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)

Question 6

Teatment for patients with peripheral T-cell lymphomas with CD30 expression

Answer 6

Brentuximab vedotin (BV)

Clinical trial: ECHELON 2

Question 7

The toxicity profile of BV-CHP was similar to CHOP but was associated with:

Answer 7

Increased risk of diarrhea

Less frequent resolution of neuropathy

Question 8

Agents approved by FDA for relapsed/refractory PTCL

Answer 8

• Romidepsin
• Belinostat
• Pralatrexate
• BV
• Allogeneic transplantation

Question 9

Characterized by PTCL-NOS that expresses two or more TFH cell markers (ICOS, CXCL13, CD10, BCL6, PD1, SAP, CCR5) by immunohistochemistry

Answer 9

PTCL-NOS with T-follicular helper (TFH) phenotype

Question 10

Translocation of ALK-negative ALCL possibly associated with a better prognosis

This mutation typically leads to reduced expression of the DUSP22 gene, which likely functions as a tumor suppressor

Answer 10

t(6;7)

Presence of p63 by immunohistochemistry delineated a higher risk population of ALK-negative ALCL.

Question 11

A translocation producing an ITK-SYK fusion gene

Suggest a potential role for SYK inhibitors

Answer 11

t(5;9)

Question 12

An ALK inhibitor, demonstrated significant activity in pediatric patients with relapsed ALK-positive ALCL

Answer 12

Crizotinib

Question 13

Drugs with have preferential activity and duration of response in patients with AITL

Answer 13

Histone deacetylase (HDAC) inhibitors, such as belinostat and romidepsin

Question 14

Both PTCL-NOS with TFH phenotype and AITL have recurrent mutations in genes involved in chromatin modification including ____

Answer 14

TET2

TET2 is involved in epigenetic control of transcription through DNA methylation and inactivating mutations of this gene were first identified in myeloid malignancies

Question 15

The most common of the mature T-cell neoplasms, representing approximately 25% to 30% of the total cases of T-cell lymphoma in Western countries.

Answer 15

PTCL-NOS

Malignant cells are often characterized by antigen aberrancy

Deletion of one or more pan–T-cell antigens is frequently observed, along with rearrangements of the TCR.

Pruritus, peripheral eosinophilia, hypercalcemia, and hemophagocytic syndrome

Question 16

The median age of diagnosis of PTCL-NOS is 60 years with a_______ predominance (2:1).

Answer 16

Male

Question 17

The majority of cases of PTCL NOS arise in

Answer 17

Lymph nodes

Question 18

The immunophenotype is typically that of a mature T cell expressing either a CD4 or CD8 phenotype, most commonly ______

Answer 18

CD4

Question 19

Initially described as angioimmunoblastic lymphadenopathy with dysproteinemia

Answer 19

Angioimmunoblastic T-cell lymphoma

The male-to-female ratio is approximately 1:1, and the median age at diagnosis is approximately 65–70 years.

Common features at presentation include B symptoms (fever, drenching sweats, and weight loss), generalized lymphadenopathy, rash, polyclonal hypergammaglobulinemia, blood eosinophilia, and autoimmune hemolytic anemia (direct Coombs positive).

Question 20

Characterized histologically by effacement of the normal lymphoid architecture with a pleomorphic cellular infiltrate and proliferation of small arborizing blood vessels

Loss of germinal centers and extensive intranodal neovascularization and expansion of the follicular dendritic cell meshwork (CD21).

Answer 20

ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA

Scattered EBV+ B cells are almost always present

Question 21

Marker typical for AITL, in approximately 90% of cases.

Answer 21

CD10

The malignant cells are CD4+ αβ T-cells with TCR-β and -γ rearrangements

Abnormal karyotypes involving the X chromosome and chromosomes 1, 3, and 5 are frequently found in AITL.

Question 22

Most patients with AITL are treated with

Answer 22

CHOP-based regimens

The optimal initial therapy for patients with AITL remains unclear

Question 23

A CD30+ peripheral T-cell neoplasm, provisionally subdivided into those that are ALK positive (60–70%) or negative (30–40%)

Answer 23

ANAPLASTIC LARGE CELL LYMPHOMA

Question 24

Ninety percent of children with ALCL are ALK ________

Answer 24

ALK positive

The median age of ALK-positive ALCL is 30–40 years old.

Question 25

Patients with ALK-_________ ALCL tend to be **younger** and have a **better performance status** and **lower serum LDH levels.** The most chemosensitive of the T-cell lymphomas

Answer 25

ALK-positive ## Footnote Approximately **8% to 12%** of patients with ALK-positive ALCL have morphologic evidence of **marrow involvement.**

Question 26

Patients with ALK-_________ ALCL tend to be **older**, with **higher LDH values** and a **worse performance status**

Answer 26

ALK-negative ## Footnote **Extranodal** presentations are more common in the ALK-negative population, and include sites such as the **marrow, liver, lung, and skin but rarely the CNS**

Question 27

This disorder is characterized by **ALK-negative ALCL** associated with **textured saline and silicone breast implants.**

Answer 27

Breast implant–associated anaplastic large cell lymphoma ## Footnote The vast majority of patients present **swelling of the breast** associated with a **seroma** and presented with an **effusion within the breast** and less frequently with a distinct breast mass.

Question 28

Three morphologic variants of ALCL based on the size of the neoplastic and admixed reactive cells.

Answer 28

* Common type * Small cell variant * Lymphohistiocytic variant

Question 29

**ALK-positive ALCL** is characterized by a nonrandom_________ translocation resulting in fusion of the **NPM and ALK genes**.

Answer 29

t(2;5) (p23;q35) ## Footnote ALK immunoreactivity is a highly specific marker for this disease.

Question 30

Pan-T antigens

Answer 30

CD2, CD2, CD4, CD5, and CD7

Question 31

Genes are typically overexpressed in ALK-positive ALCL

Answer 31

CEBPB, PTPN12, SERPINA1, and BCL6

Question 32

Genes are typically overexpressed in ALK-negative ALCL

Answer 32

CCR7, CNTFR, interleukin (IL)-21, and IL-22

Question 33

Associated with favorable prognosis among ALK-negative ALCL similar to ALK-positive ALCL

Answer 33

DUSP22 CD56 ## Footnote But those with **TP63** expression are associated with an especially poor prognosis

Question 34

The most chemosensitive of the T-cell lymphomas

Answer 34

ALK-positive ALCL

Question 35

Previous treatment for ALCL

Answer 35

CHOP-based therapy

Question 36

The new standard of care in patients with previously untreated ALK-positive or ALK-negative ALCL

Answer 36

BV-CHP

Question 37

An **inhibitor of ALK tyrosine kinase** that is FDA approved for the treatment of ALK-positive non–**small cell lung cancer**, has demonstrated encouraging responses in small series of **ALK-positive ALCL**, leading to ongoing trials in relapsed/refractory ALCL

Answer 37

Crizotinib

Question 38

ALK-_________ ALCL typically presents with unfavorable features, including **stages III and IV disease, B symptoms, high IPI scores, high serum LDH levels, and expression of TP63.**

Answer 38

ALK-negative ALCL

Question 39

A mature T-cell lymphoma that presents within the **gastrointestinal (GI) tract.**

Answer 39

Enteropathy-associated intestinal T-cell lymphoma (EATL) ## Footnote The median patient age at diagnosis is **55–65 years** with a slight **male** predisposition.

Question 40

EATL comprises **60% to 80%** of cases, is most common in patients who have underlying_______________, and is strongly associated with the human leukocyte antigen____________

Answer 40

Celiac disease (HLA)-DQ2 haplotype

Question 41

Present in 20% to 40% of cases, is less frequently associated with celiac sprue and the HLA-DQ2 haplotype.

Answer 41

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)

Question 42

EATL typically presents with

Answer 42

Acute abdominal symptoms Ulcerative lesions of the jejunum or ileum

Question 43

The two types of EATL are recognized on the basis of the specific immunophenotype:

Answer 43

EATL: CD56 negative MEITL: CD56 positive

Question 44

The histology of EATL demonstrates

Answer 44

Medium to large tumor cells with round or angulated vesicular nuclei, prominent nucleoli, and pale-staining cytoplasm

Question 45

EATL characteristically demonstrates the following immunophenotype:

Answer 45

Positive for CD3, CD7, CD103, and usually CD30 ; perforin, granzyme B, and TIA-1 Negative for CD4, CD5, CD8, and CD56

Question 46

MEITL characteristically demonstrates the following immunophenotype:

Answer 46

Positive for CD3, CD8, CD56, TCR-γ/δ or TCR-α/β Negative for CD4, CD30

Question 47

Treatment used most widely for both EATL and MEITL

Answer 47

CHOP chemotherapy

Question 48

Adverse prognostic factors with EATL

Answer 48

* History of celiac sprue * A large tumor mass (≥5 cm) at diagnosis * An elevated LDH * A nonambulatory performance status

Question 49

**ADULT T-CELL LEUKEMIA/LYMPHOMA** is an uncommon lymphoproliferative neoplasm of mature _____________T-cells

Answer 49

CD4+CD25+ T-cells

Question 50

ATL is caused by infection with the

Answer 50

Retrovirus HTLV-1 ## Footnote HTLV-1 is transmitted through breastfeeding, blood products, and unprotected sexual intercourse.

Question 51

ATL has cells classically have a leukemic _____________ appearance

Answer 51

“flower-cell” appearance

Question 52

At least ____% of circulating abnormal T lymphocytes are required to diagnose ATL in **patients without histologically proven tumor lesions.**

Answer 52

5%

Question 53

The mean age of patients with adult T-cell leukemia/lymphoma is 62 years, _________________ predominance.

Answer 53

Without a gender predominance

Question 54

Clinical variants of ATL

Answer 54

* Acute variant 60% * Lymphoma variant 20% * Chronic * Smoldering

Question 55

Variant of ATL that presents with a predominance of **skin lesions or lung infiltration without visceral or marrow disease** and minimal blood involvement (<5% of lymphocytes).

Answer 55

Smoldering form of adult T-cell leukemia/lymphoma

Question 56

Variant of ATL that present with **leukocytosis** **with lymphadenopathy and organomegaly without an elevated LDH level or visceral involvement.**

Answer 56

Chronic ATL

Question 57

Characteristic of cells of ATL

Answer 57

Highly lobulated nuclei (**“clover leaf” or “flower-cell”** appearances) with condensed nuclear chromatin, inconspicuous nucleoli, and a mature helper T-lymphocyte immunophenotype. ## Footnote In approximately 20% of cases, nuclear lobulation is less pronounced, and the cells may be difficult to distinguish from Sézary cells.

Question 58

Immunophenotype of ATL

Answer 58

Positive: CD2, CD4 and CD5, CD45RO, CD29, and TCR-αβ; Negative for CD7, CD8, and CD26; and show reduced CD3 expression The lymphocytic activation markers HLA-DP, -DQ, and -DR and IL-2Rα (CD25) are always present, whereas terminal deoxy-nucleotidyl transferase is typically absent.

Question 59

The prognosis in ATL remains **poor** with a median survival time of less than ________ year for patients with aggressive subtypes

Answer 59

1 year ## Footnote **Inadequacy of CHOP in this disease** The role of antiviral therapy remains controversial.

Question 60

Drug has been approved in Japan for the treatment of **relapsed or refractory adult T-cell leukemia-lymphoma** and is compendium listed in the United States by the National Comprehensive Cancer Network for the same patient population.

Answer 60

Mogamulizumab (anti-CCR4 monoclonal antibody)

Question 61

A rare lymphoma that infiltrates the spleen, liver, and marrow In the majority of cases, cells consist of **mature γ/δ T cells**; however, α/β HSTCL has also been reported.

Answer 61

Hepatosplenic T-cell lymphoma (HSTCL) ## Footnote HSTCL is a rare lymphoma, representing **3%** of all T-cell lymphomas. This disease typically occurs in **young men** at a median age of **35 years.** The optimal therapy for HSTCL is not known.

Question 62

Risk factors for Hepatosplenic T-cell lymphoma (HSTCL)

Answer 62

* Immunosuppression after solid-organ transplantation or * Use of anti–tumor necrosis factor-α or thiopurine agents

Question 63

Common presentation of HSTCL

Answer 63

Isolated hepatosplenomegaly without lymphadenopathy ## Footnote Frequently accompanied by cytopenias, B symptoms, and an elevated serum LDH level.

Question 64

Immunophenotype of Hepatosplenic T-cell lymphoma (HSTCL)

Answer 64

Positive: CD3, CD56, and TCR-δ Negative for CD4 and usually CD8 ## Footnote **Clonal rearrangement of the TCR-γ gene** is usually present, and in most cases, the lymphoma cells have an **isochromosome 7q [i7(q10)]** along with **trisomy 8**, which also may be seen in the αβ variant of this disease.

Question 65

Other name for **Extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type**

Answer 65

Lethal midline granuloma, malignant granuloma, or angiocentric lymphoma ## Footnote ENKTL represents approximately **2% to 9%** of T-cell lymphomas. The disease typically afflicts **middle-aged men**, with a median age of **50 years** at diagnosis, but it may also affect children.

Question 66

# TRUE OR FALSE ENKTLs are almost exclusively extranodal.

Answer 66

TRUE ENKTLs are almost exclusively extranodal. ## Footnote Initial sites involved are often the **nose and nasopharynx** and occasionally the paranasal sinuses, tonsils, Waldeyer ring, and oropharynx.

Question 67

Histopathology of ENKTL

Answer 67

Angiocentric plesiomorphic small- or medium-size atypical lymphoid cells with **vascular invasion and ischemic tissue necrosis.**

Question 68

Immunophenotype of ENKTLs

Answer 68

Positive: CD2 and CD7 ; CD16, CD56, cytoplasmic CD3ε, and CD57 Negative for surface CD3

Question 69

Treatment for localized NK-/T-cell lymphoma

Answer 69

Combined chemotherapy and radiation therapy

Question 70

Drug that has a major single-agent activity in NK-/T-cell lymphomas and is incorporated into most modern regimens for this disease.

Answer 70

L-Asparaginase ## Footnote In patients with localized ENKTL, it is standard to consolidate asparaginase-based chemotherapy with radiation therapy. REGIMENS SMILE (dexamethasone, methotrexate, ifosfamide, Lasparaginase, and etoposide) Gemcitabine, oxaliplatin, and Lasparaginase (GELOX)

Question 71

A primary cutaneous T-cell lymphoma presenting with **painful subcutaneous nodules**. Subcutaneous nodules that typically begin in the extremities

Answer 71

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) ## Footnote A disorder of adults with an average age at diagnosis in the **mid to late 30s**, although cases have also been reported in children. SPTL has a **female** predominance with a male-to-female ratio of 0.5.144

Question 72

Characteristics of lesions of Subcutaneous panniculitis-like T-cell lymphoma (SPTL)

Answer 72

**Atypical lymphoid cells and reactive histiocytes** with admixed adipose tissue often associated with **coagulation necrosis.**

Question 73

Histologically, the cells of SPTL express an ________ phenotype.

Answer 73

α/β phenotype ## Footnote The **γ/δ phenotype** of this disease is now classified as **cutaneous γ/δ T-cell lymphoma.** Composed of mature **CD8+ αβ cytotoxic T cells** that express **TIA-1, granzymes, and perforin genes.**

Question 74

An anti–IL-2 receptor antibody coupled to diphtheria toxin, has been reported in two patients with evidence of activity in SPTCL

Answer 74

Denileukin diftitox