103 Mature T-Cell and Natural Killer Cell Lymphomas Flashcards
Whereas B-cell lymphomas are often characterized by a specific immunophenotypic profile, T-cell lymphomas are often characterized by
Antigen aberrancy
In establishing the diagnosis of T-cell NHL, it is important to exclude a reactive process
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
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.
Prognostic index for T-cell lymphoma (PIT) includes
Age, performance status, LDH level, and marrow involvement
IPTCLP score
Albumin, performance status, stage, and absolute neutrophil count
Most commonly used backbone for initial therapy of patients with PTCL
CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)
Teatment for patients with peripheral T-cell lymphomas with CD30 expression
Brentuximab vedotin (BV)
Clinical trial: ECHELON 2
The toxicity profile of BV-CHP was similar to CHOP but was associated with:
Increased risk of diarrhea
Less frequent resolution of neuropathy
Agents approved by FDA for relapsed/refractory PTCL
- Romidepsin
- Belinostat
- Pralatrexate
- BV
- Allogeneic transplantation
Characterized by PTCL-NOS that expresses two or more TFH cell markers (ICOS, CXCL13, CD10, BCL6, PD1, SAP, CCR5) by immunohistochemistry
PTCL-NOS with T-follicular helper (TFH) phenotype
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
t(6;7)
Presence of p63 by immunohistochemistry delineated a higher risk population of ALK-negative ALCL.
A translocation producing an ITK-SYK fusion gene
Suggest a potential role for SYK inhibitors
t(5;9)
An ALK inhibitor, demonstrated significant activity in pediatric patients with relapsed ALK-positive ALCL
Crizotinib
Drugs with have preferential activity and duration of response in patients with AITL
Histone deacetylase (HDAC) inhibitors, such as belinostat and romidepsin
Both PTCL-NOS with TFH phenotype and AITL have recurrent mutations in genes involved in chromatin modification including ____
TET2
TET2 is involved in epigenetic control of transcription through DNA methylation and inactivating mutations of this gene were first identified in myeloid malignancies
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.
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
The median age of diagnosis of PTCL-NOS is 60 years with a_______ predominance (2:1).
Male
The majority of cases of PTCL NOS arise in
Lymph nodes
The immunophenotype is typically that of a mature T cell expressing either a CD4 or CD8 phenotype, most commonly ______
CD4
Initially described as angioimmunoblastic lymphadenopathy with dysproteinemia
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).
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).
ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA
Scattered EBV+ B cells are almost always present
Marker typical for AITL, in approximately 90% of cases.
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.
Most patients with AITL are treated with
CHOP-based regimens
The optimal initial therapy for patients with AITL remains unclear
A CD30+ peripheral T-cell neoplasm, provisionally subdivided into those that are ALK positive (60–70%) or negative (30–40%)
ANAPLASTIC LARGE CELL LYMPHOMA
Ninety percent of children with ALCL are ALK ________
ALK positive
The median age of ALK-positive ALCL is 30–40 years old.
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
ALK-positive
Approximately 8% to 12% of patients with ALK-positive ALCL have morphologic evidence of marrow involvement.
Patients with ALK-_________ ALCL tend to be older, with higher LDH values and a worse performance status
ALK-negative
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
This disorder is characterized by ALK-negative ALCL associated with textured saline and silicone breast implants.
Breast implant–associated anaplastic large cell lymphoma
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.
Three morphologic variants of ALCL based on the size of the neoplastic and admixed reactive cells.
- Common type
- Small cell variant
- Lymphohistiocytic variant
ALK-positive ALCL is characterized by a nonrandom_________ translocation resulting in fusion of the NPM and ALK genes.
t(2;5) (p23;q35)
ALK immunoreactivity is a highly specific marker for this disease.
Pan-T antigens
CD2, CD2, CD4, CD5, and CD7
Genes are typically overexpressed in ALK-positive ALCL
CEBPB, PTPN12, SERPINA1, and BCL6
Genes are typically overexpressed in ALK-negative ALCL
CCR7, CNTFR, interleukin (IL)-21, and IL-22
Associated with favorable prognosis among ALK-negative ALCL similar to ALK-positive ALCL
DUSP22
CD56
But those with TP63 expression are associated with an especially poor prognosis
The most chemosensitive of the T-cell lymphomas
ALK-positive ALCL
Previous treatment for ALCL
CHOP-based therapy
The new standard of care in patients with previously untreated ALK-positive or ALK-negative ALCL
BV-CHP
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
Crizotinib
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.
ALK-negative ALCL
A mature T-cell lymphoma that presents within the gastrointestinal (GI) tract.
Enteropathy-associated intestinal T-cell lymphoma (EATL)
The median patient age at diagnosis is 55–65 years with a slight male predisposition.
EATL comprises 60% to 80% of cases, is most common in patients who have underlying_______________, and is strongly associated with the human leukocyte antigen____________
Celiac disease
(HLA)-DQ2 haplotype
Present in 20% to 40% of cases, is less frequently associated with celiac sprue and the HLA-DQ2 haplotype.
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
EATL typically presents with
Acute abdominal symptoms
Ulcerative lesions of the jejunum or ileum
The two types of EATL are recognized on the basis of the specific immunophenotype:
EATL: CD56 negative
MEITL: CD56 positive
The histology of EATL demonstrates
Medium to large tumor cells with round or angulated vesicular nuclei, prominent nucleoli, and pale-staining cytoplasm
EATL characteristically demonstrates the following immunophenotype:
Positive for CD3, CD7, CD103, and usually CD30 ; perforin, granzyme B, and TIA-1
Negative for CD4, CD5, CD8, and CD56
MEITL characteristically demonstrates the following immunophenotype:
Positive for CD3, CD8, CD56, TCR-γ/δ or TCR-α/β
Negative for CD4, CD30
Treatment used most widely for both EATL and MEITL
CHOP chemotherapy
Adverse prognostic factors with EATL
- History of celiac sprue
- A large tumor mass (≥5 cm) at diagnosis
- An elevated LDH
- A nonambulatory performance status
ADULT T-CELL LEUKEMIA/LYMPHOMA is an uncommon lymphoproliferative neoplasm of mature _____________T-cells
CD4+CD25+ T-cells
ATL is caused by infection with the
Retrovirus HTLV-1
HTLV-1 is transmitted through breastfeeding, blood products, and unprotected sexual intercourse.
ATL has cells classically have a leukemic _____________ appearance
“flower-cell” appearance
At least ____% of circulating abnormal T lymphocytes are required to diagnose ATL in patients without histologically proven tumor lesions.
5%
The mean age of patients with adult T-cell leukemia/lymphoma is 62 years, _________________ predominance.
Without a gender predominance
Clinical variants of ATL
- Acute variant 60%
- Lymphoma variant 20%
- Chronic
- Smoldering
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).
Smoldering form of adult T-cell leukemia/lymphoma
Variant of ATL that present with leukocytosis with lymphadenopathy and organomegaly without an elevated LDH level or visceral involvement.
Chronic ATL
Characteristic of cells of ATL
Highly lobulated nuclei (“clover leaf” or “flower-cell” appearances) with condensed nuclear chromatin, inconspicuous nucleoli, and a mature helper T-lymphocyte immunophenotype.
In approximately 20% of cases, nuclear lobulation is less pronounced, and the cells may be difficult to distinguish from Sézary cells.
Immunophenotype of ATL
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.
The prognosis in ATL remains poor with a median survival time of less than ________ year for patients with aggressive subtypes
1 year
Inadequacy of CHOP in this disease
The role of antiviral therapy remains controversial.
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.
Mogamulizumab (anti-CCR4 monoclonal antibody)
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.
Hepatosplenic T-cell lymphoma (HSTCL)
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.
Risk factors for Hepatosplenic T-cell lymphoma (HSTCL)
- Immunosuppression after solid-organ transplantation or
- Use of anti–tumor necrosis factor-α or thiopurine agents
Common presentation of HSTCL
Isolated hepatosplenomegaly without lymphadenopathy
Frequently accompanied by cytopenias, B symptoms, and an elevated serum LDH level.
Immunophenotype of Hepatosplenic T-cell lymphoma (HSTCL)
Positive: CD3, CD56, and TCR-δ
Negative for CD4 and usually CD8
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.
Other name for Extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type
Lethal midline granuloma, malignant granuloma, or angiocentric lymphoma
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.
TRUE OR FALSE
ENKTLs are almost exclusively extranodal.
TRUE
ENKTLs are almost exclusively extranodal.
Initial sites involved are often the nose and nasopharynx and occasionally the paranasal sinuses, tonsils, Waldeyer ring, and oropharynx.
Histopathology of ENKTL
Angiocentric plesiomorphic small- or medium-size atypical lymphoid cells with vascular invasion and ischemic tissue necrosis.
Immunophenotype of ENKTLs
Positive: CD2 and CD7 ; CD16, CD56, cytoplasmic CD3ε, and CD57
Negative for surface CD3
Treatment for localized NK-/T-cell lymphoma
Combined chemotherapy and radiation therapy
Drug that has a major single-agent activity in NK-/T-cell lymphomas and is incorporated into most modern regimens for this disease.
L-Asparaginase
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)
A primary cutaneous T-cell lymphoma presenting with painful subcutaneous nodules.
Subcutaneous nodules that typically begin in the extremities
Subcutaneous panniculitis-like T-cell lymphoma (SPTL)
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
Characteristics of lesions of Subcutaneous panniculitis-like T-cell lymphoma (SPTL)
Atypical lymphoid cells and reactive histiocytes with admixed adipose tissue often associated with coagulation necrosis.
Histologically, the cells of SPTL express an ________ phenotype.
α/β phenotype
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.
An anti–IL-2 receptor antibody coupled to diphtheria toxin, has been reported in two patients with evidence of activity in SPTCL
Denileukin diftitox
