Nodular T Cell

1. Diagnostic approach to nodal
T-cell lymphoma

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3. • Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of
malignancies of the immune system, comprising more than 40
entities with specific clinical, morphologic,immunophenotypic, and
molecular characteristics.
• In the western world, NHLs originate from B lymphocytes in 85–90%
of cases and from lymphoid T cells and natural killer cells (NK)in 10–
15% of cases
• T-cell lymphomas represent a higher proportion of NHL cases in Asian
countries, accounting for upto 25% of these neoplasms

4. • NHLs that originate from mature T lymphocytes or NK cells are
recognized as peripheral T-cell lymphomas (PTCL)
• Primary nodal PTCLs
-peripheral T-cell lymphoma not otherwise specified (PTCL-NOS)
- angioimmunoblastic T-cell lymphoma (AITL)
- anaplastic large-cell lymphoma-anaplastic lymphoma kinase (ALK)
positive (ALCL-ALK+)
- anaplastic large-cell lymphoma-ALK negative (ALCL-ALK−)

5. World Health Organization classification of peripheral
natural killer (NK)/T-cell lymphomas

6. • Primary cutaneous lymphomas
• Mycosis fungoides and Sézary syndrome
• Primary cutaneous CD30+ T-cell lymphoproliferative disease
• Primary cutaneous peripheral T-cell lymphomas (PTCLs)
• Nodal peripheral T-cell lymphomas (PTCL)
• Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS)
• Angioimmunoblastic T-cell lymphoma (AITL)
• Anaplastic large-cell lymphoma (ALCL) anaplastic lymphoma kinase
(ALK) positive
• Anaplastic large-cell lymphoma (ALCL) ALK negative (provisional)
World Health Organization classification
of peripheral natural killer (NK)/T-cell
lymphomas

7. • Extranodal peripheral T-cell lymphomas
• Extranodal NK-T-cell lymphomanasal type
• Enteropathy-associated T-cell lymphoma (EATL)
• Hepatosplenic T-cell lymphoma (HSTL)
• Subcutaneous panniculitis-like T-cell lymphoma (SPTCL)
• Epstein–Barr virus (EBV)-positive T-cell lymphoproliferative childhood
disorders
• Widespread or leukemic
• T-cell prolymphocytic leukemia
• T-cell large granular lymphocytic leukemia
• NK-cell leukemia
• Adult T-cell leukemia/lymphoma

8. Relative frequencies of mature T-cell lymphoma
subtypes in an adult patient population

9. • A 68-year-old Japanese male was indicated a chest radiographic
abnormality in the right upper lung field by routine health check-up.was
diagnosed with right upper lobe pneumonia.
• Despite antibiotic treatment, chest radiographic abnormality got worse A
general physical examination revealed an enlarged lymph node in the right
axillary region.
• His lymph node was firm, unmovable and non-tender and measured
3.0×3.0 cm.
• PET revealed an abnormal FDG accumulation in the subcutaneous nodules
on the mandibular and left chest wall, a lymph nodes (submandibular, right
axillary and mediastinal)

10. PET revealed an abnormal FDG accumulation in the subcutaneous nodules on
the mandibular region and lymphnodes

11. • Immunohistochemical study revealed focal positive staining for
CD3,CD4, and negative staining for CD8, and EBV
Diffuse proliferationof atypical
medium sized lymphoid cells
Diffuse expression of CD3 by the
neoplastic lymphoid cells

12. Peripheral T-cell lymphoma, NOS
• Peripheral T-cell lymphoma (PTCL),NOS, is a heterogeneous category
of nodal and extranodal mature T-cell lymphomas that do not
correspond to any of the specifically defined entities of mature T-cell
lymphoma in the current classification
• account for approximately 30% of PTCLs in western countries
• Most patients are adults
• These lymphomas are very rare in children
• Male-to-female ratio is 2:1.

13. • Etiology
• The infection of neoplastic cells by EBV is reported in a small number
of cases
• Localization
• Peripheral lymph node involvement is common
• Secondary involvement of the bone marrow, liver, spleen, and
extranodal tissues seen
• Extranodal presentations most commonly in the skin and
gastrointestinal tract seen

14. • Clinical features
• Patients most often present with lymph node enlargement, and most have
eosinophilia, pruritus, or (rarely) haemophagocytic syndrome
• elevated lactate dehydrogenase (LDH) levels, high tumor burden, advanced
disease (Stage III or IV), and poor performance status
• Microscopy
• In the lymph node, lymphomas show paracortical or diffuse infiltrates with
effacement of the normal architecture
• The cytological spectrum varies from polymorphous to monomorphic
• Mostly consist of numerous medium-sized and/or large cells with
irregular,pleomorphic, hyperchromatic, or vesicular nuclei, prominent nucleoli,
and many mitotic figures
• Clear cells and Reed-Sternberg-like cells can also be seen

15. • Inflammatory background including small lymphocytes, eosinophils,
plasma cells, large B cells and clusters of epithelioid histiocytes noted
• Epithelioid histiocytes are seen numerous in the lymphoepithelioid
variant

16. • Extranodal involvement shows diffuse infiltrates composed of similar
cells.
• In the skin, the lymphomatous population infiltrates the dermis and
subcutis,and often produce nodules
• In the spleen, solitary or multiple fleshy nodules to diffuse white pulp
involvement with colonization of the periarteriolar sheaths or, in
some cases, predominant infiltration of the red pulp seen

17. Large lymphoid cells with
pleomorphic ,irregular nuclei
prominent nucleoli and clear cell
features

18. Nuclei are round and monomorphic in
appearence
Eosinophils and numerous vessels seen in
between the neoplastic cells

19. Rich histiocytic background
This variant positive for CD8,CD30 stains RS –like
cells,CD68 shows numerous histiocytes

20. Genetic Profile
• T-cell receptor (TCR) genes are clonally rearranged in most cases and
is seen by polymerase chain reaction
• These neoplasms are associated with complex karyotypes and
recurrent chromosomal gains and losses
• PTCL-NOS, cases characterized by the expression of TBX21 (also
known as T-BET) or GATA3
• Gene expression profiling and microRNA profiling studies are helpful
in distinguishing AITL ,ALK+ and ALK- ALCL from PTCL-NOS

21. Differentials
• PTCL-NOS which express the CD30 marker can be distinguished from
ALK- ALCl on phenotypic and morphologic profile ,also the latter
expresses epithelial membrane antigens (EMA) and contains cytotoxic
granules
• Classical Hodgkin’s lymphoma (HL) can be by distinguished by the
expression of CD15, PAX-5, and Epstein–Barr virus (EBV)

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• highly aggressive lymphomas with a poor response to therapy
• prncxaaaaognosis depends on stage and International Prognostic
Index(IPI) score
• Poor prognostic factors-
• Involvement of the bone marrow
• Ki-67 proliferation index > 70%
• EBV positivity, NF-kappaB pathway deregulation
• GATA3 or cytotoxic profile
• CD30 expression

24. Angioimmunoblastic T-cell lymphoma
• Angioimmunoblastic T-cell lymphoma (AITL) is a neoplasm of mature
T follicular helper (TFH) cells characterized by systemic disease and a
polymorphous infiltrate involving lymph nodes, with a prominent
proliferation of high endothelial venules (HEVs) and follicular
dendritic cells (FDCs)

25. • occurs in middle-aged and elderly individuals
• higher incidence in males than in females
• most common specific subtypes of PTCL
• Accounts 15-30% of noncutaneous T-cell lymphomas and 1-2% of all
non-Hodgkin lymphomas

26. • Etiology
• The strong association with EBV infection suggests a possible role for
the virus in the etiology
• The primary site of disease is the lymphnode
• all patients present with generalized lymphadenopathy
• The spleen, liver, skin, and bone marrow are also frequently involved

27. • Clinical features
• AITL typically presents with advanced stage disease
• generalized lymphadenopathy,
• hepatosplenomegaly, systemic symptoms, and polyclonal
hypergammaglobulinaemia
• Skin rash, often with pruritus pleural effusion, arthritis, and ascites
frequently present
• Laboratory findings
• Circulating immune complexes, cold agglutinins
• with haemolytic anaemia, positive rheumatoid factor
• anti- smooth muscle antibodies

28. • Microscopy
• characterized by partial or total effacement of the lymph node
architecture,often with perinodal infiltration but sparing of the peripheral
cortical sinuses
• the neoplastic T cells are small to medium-sized lymphocytes,with clear to
pale cytoplasm, distinct cell membranes, and minimal cytological atypia.
• Vascularity is often prominent, with arborization of HEVs in the paracortex
• The neoplastic cells are present in a polymorphous inflammatory
background containing variable numbers of reactive
lymphocytes,histiocytes, plasma cells, and eosinophils

29. Pattern -1
bare, hyperplastic follicles with paracortical expansion and
marked vascular proliferation
associated with perifollicular or atypical lymphoid cells

30. Pattern-2
depleted/atrophic follicles and marked perifollicular
expansion of clear cells

31. Pattern-3
effacement of normal architecture and marked vascular
proliferation associated with aggregates of atypical
lymphoid cells

32. • lmmunophenotype
• The neoplastic T cells express most pan-T-cell antigens such as CD3,
CD2, and CD5
• the tumour cells show the immunophenotype of normal TFH cells,
expressing CD10, CXCL13, ICOS, BCL6, and PD1 (CD279) in 60-100% of
cases
• helpful in distinguishing AITL from atypical paracortical hyperplasia
and other PTCLs
• FDC meshworks expressing CD21, CD23, and CD35 are expanded
• with an extrafollicular pattern, usually surrounding the HEVs

33. • CD10 staining highlights neoplastic T cells
surrounding the hyperplastic germinal centres

34. Angioimmunoblastic T-cell lymphoma
pattern 3, expressing PD1.

35. CD21 &CD3

36. CD10 &CD 79a

37. Genetics
• Karyotypic aberrations occur in 70–80% of cases
• mainly trisomy of chromosome 3 and 5, and an additional X
chromosome noted

38. • Prognosis and predictive factors
• Overall the prognosis is poor, with a median survival of < 3 years
• male sex, mediastinal lymphadenopathy,and anaemia adversely
affects overall survival

39. A 16-year-old boy presented with an eight-month history of pain in his
dorsal spine and with a late one-month history of ache in his left articulatio
coxae accompanied with the limitation of motion
• Physical examination revealed lymphadenopathy in the neck and right
axillary region
• No fever, cutaneous lesions, hepatomegaly or splenomegaly was found
• Laboratory tests showed elevated CRP of 87.6 mg/L and ESR (Erythrocyte
sedimentation rate) of 66.0 mm/h
• EBV (Epstein-Barr virus) DNA (deoxyribonucleic acid) was elevated to
1.76E+01 copies/mL
• HLA-B27 was negative, and the serum LDH (lactate dehydrogenase) level
was within normal range

40. • CT and MRI scans reported a bone destruction with measuring
4.3×1.8 cm in the left iliac bone, surrounded by sclerotic bones and
swelling soft tissues
• Abdominal CT found some enlarged retroperitoneal lymphoid nodes
and a mild splenomegaly

41. • On microscopy, effacement of normal architecture by granulomatous
tissues and mixed cells including lymphocytes, eosinophil
granulocytes, plasma cells with a few large atypical cells with horse
shaped nuclei seen
• On IHC, these cells were positively stained with CD30, Ki-67, ALK-1
and EMA but negatively with CD45, CD15, mum-1, PAX-5
• Diagnosis of ALK-positive ALCL was decided pathologically

42. Anaplastic large cell lymphoma,
ALK-positive
• ALK-positive (ALK+) anaplastic large cell lymphoma (ALCL) is a T-cell
lymphoma consisting of lymphoid cells that are usually large and have
abundant cytoplasm and pleomorphic, often horseshoe-shaped
nuclei, with a chromosomal translocation involving the ALK gene and
expression of ALK protein and CD30
• The most commonly involved extranodal sites include the skin, bone,
soft tissue,lungs, and liver

43. • ALK+ ALCL constitutes approximately 3% of adult non-Hodgkin
lymphomas and 10-20% of childhood lymphomas
• is most frequent in the first three decades of life
• Male predominance noted with a male-to-female ratio of 1.5:1.

44. • Clinical features
• Most patients (70%) present with advanced (stage Ill -IV) disease with
peripheral or abdominal lymphadenopathy
• often associated with extranodal infiltrates and involvement of the
bone marrow
• Most have B symptoms, especially high fever

45. Microscopy
• Morphologically, ALK+ ALCLs range from small-cell neoplasms to very
large cells which predominate
• Several morphological patterns are recognized
• hallmark cells seen and they are present in all morphological variants
• The hallmark cells are typically large, with eccentric,horseshoe-
shaped, or kidney-shaped nuclei, often with an eosinophilic region
• The nuclear chromatin is usually finely clumped or dispersed, with
multiple small, basophilic nucleoli

46. • The small-cell pattern (5-10%) shows a predominant population of
small to medium-sized neoplastic cells with irregular nuclei
• Some cases,most of the cells have pale cytoplasm and centrally
located nucleus these are referred to as fried-egg cells

47. • The Hodgkin-like pattern (3%) is characterized by morphological
features mimicking nodular sclerosis classic Hodgkin lymphoma
Tumour nodules surrounded by fibrous
bands
Tumour cells resembling
Reed-Sternberg cell

48. • The lymphohistiocytic pattern (10%) is characterized by tumour cells
admixed with a large number of reactive histiocytes
• Occasional cases may have a hypocellular appearance, with a myxoid
or oedematous background
• Spindle cells may be prominent in such cases and may simulate
sarcoma in cases presenting in soft tissue
• In 15% of cases, more than one pattern can be seen in a single lymph
node biopsy, this is called the composite pattern

49. ALCL showing sarcomatous
features Hypocellular ALCL

50. Immunophenotype
• The tumour cells are positive for CD30 on the cell membrane and in
the Golgi region
• In the lymphohistiocytic and small-cell patterns,the strongest CD30
expression is also present in the larger tumour cells,and cluster
around blood vessels
• ALK staining of large cells is both cytoplasmic and nuclear

51. • Most ALK+ ALCLs are positive for EMA, CD2,CD5, and CD4
• Most cases exhibit positivity for the cytotoxic antigens TIA1,granzyme
B, and or perforin
• In some cases, only a proportion of malignant cells are positive CD3
and is negative in > 75% of cases
• CD8 is usually negative
• ALK+ ALCLs are BCL2-negative and are also consistently negative for
EBV

52. The lymph node architecture is obliterated by malignant
cells

53. Hallmark cell showing eccentric
kidney-shaped nuclei
CD 30

54. Genetics
• ALK abnormalities present
• T(2;5)(p23;q35)/NPM-ALK most common (80%)
• Monoclonal TCR gene rearrangements

55. Prognosis
• ALK+ ALCL has better prognosis than that of ALK- ALCL

56. • A 33-year-old man presented to hospital with typical clinical
manifestations of tuberculous lymphadenitis, with negative tests for
both acid-fast bacilli and fungi, and negative polymerase chain
reaction for Mycobacterial tuberculosis complex.
• The disease was not responding to anti-tuberculosis treatment and he
developed both pericardial effusion and progressive
lymphadenopathy
• Large lymphoma cells were evident in the pericardial effusion, and a
review of the previous lymph node biopsies confirmed the existence
of ALK-positive anaplastic large cell lymphoma and tuberculous
lymphadenitis

57. Typical caseating granulomas
(arrows) at low magnification
typical epithelioid histiocytes
in granulomas at high
magnification
some scattered activated
lymphoid cells outside the
granuloma

58. Typical fibrocaseous granulomas
in black rectangular box and
lymphoma area in red
oval at low magnification
large lymphoma cells CD30+ lymphoma cells
ALK+ lymphoma cells

59. • “Inattentional blindness” or “Perceptual blindness”
• Lymphoma cells may produce some cell products or cytokines that
directly induce granulomatous reaction or that indirectly activate
immune cells involved in the formation of granulomatous reaction

60. Differential diagnosis
• ALK- ALCL
• Nodular sclerosis Hodgkin Lymphoma
• PTCL-NOS
• Burkitt lymphoma
• Sinusoidal DLBCL

61. CD30

62. Anaplastic large cell lymphoma,
ALK-negative
• ALK-negative (ALK- ) anaplastic large cell lymphoma (ALCL) is defined
as a CD30+ T-cell neoplasm that is not reproducibly distinguishable on
morphological grounds from ALK-positive (ALK+) ALCL, but lacks ALK
protein expression
• The peak incidence of ALK- ALCL is in adults (aged 40- 65 years)
• Male-to-female ratio of 1.5:1
• ALK- ALCL involves both lymph nodes and extranodal tissues (e.g. the
bone,soft tissue, and skin)
• Extranodal sites are less commonly involved than in ALK+ ALCL

63. • Most patients present with advanced (stage Ill-IV) disease, with peripheral and/or
abdominal lymphadenopathy and B symptoms
• Microscopy-
• nodal or other tissue architecture is effaced by solid, cohesive sheets of
neoplastic cells, these are large pleomorphic cells,sometimes containing
prominent nucleoli
• Multinucleated cells, including wreathlike cells, and mitotic figures are seen.
• Hallmark cells with eccentric, horseshoe-shaped, or kidney shaped nuclei noted
• If lymph node architecture is preserved, the neoplastic cells typically grow within
sinuses or within T-cell areas
• Absence of these features suggest a diagnosis of PTCL, NOS
• Sclerosis and eosinophils may occur (D/D-CHL)

64. Anaplastic large cell
lymphoma (ALCL), ALK-
negative
Eosinophils are present (often in
clusters), but other features of
Hodgkin lymphoma are
absent
Typical morphological and
phenotypic features of ALCL,
including a hallmark cell

65. lmmunostaining for
CD30 ,cohesive
Intrasinusoidal growth pattern
CD30 shows strong
membranous positivity

66. • Immunophenotype-
• tumour cells are strongly positive for CD30, most strongly at the cell
• membrane and in the Golgi region, diffuse cytoplasmic positivity is
• also common.
• Staining should be strong and of equal intensity in all cells (to r/o PTCLs
expressing CD30)
• ALK- ALCL expresses one or more T-cell markers such as CD2 and CD3 are
more often than CD5
• CD43 almost always expressed
• CD4 is positive in a significant proportion of cases

67. • In cases that lack all T-cell/cytotoxic markers,
• CHL rich in neoplastic cells and other large cell malignancies (e.g.
embryonal carcinoma) should be ruled out
• Staining for PAX5 is useful,(CHL- weak expression
• And rare cases of ALCL (ALK- or ALK+) may express PAX5
• Clusterin is also commonly expressed in both ALK- and ALK+ ALCL, but
rarely in PTCL, NOS

68. Differential diagnosis-
- PTCL, NOS
- CHL
- Primary C-ALCL

69. • Prognosis and predictive factors
- the clinical outcome of ALK- ALCL with conventional therapy is poorer
than that of ALK+ ALCL

70. • The minimum criteria for TFH-cell phenotype is detection of at least
two (ideally three) of the TFH-cell markers in addition to CD4 is
suggested to assign a TFH-cell phenotype to a nodal CD4+ T-cell
lymphoma

71. Microscopy
• The lymph node architecture is partially or completely effaced by a
nodular/follicular proliferation of intermediate-sized monotonous
lymphoid cells with round nuclei and abunant pale cytoplasm

72. Genetic Profile-
• In the subtype with a follicular growth pattern, it is common to
observe the recurrent aberration t(5;9)(q33;q22) that produces the
oncogenic protein ITK-SYK
• these cases share some of the genetic alterations seen in AITL,
including mutations of TET2, ONMT3A, and RHOA

73. Prognosis
• Prognostic Index for T-cell Lymphomas (PIT)
• Prognostic index includes four risk factors
- Age
- serumLDH
- performance status
- histopathological involvementof the bone marrow
- Patients were stratified into four risk groups with 0, 1, 2, or more than
2 risk factors with overall survival (OS) of 62%; 53%, 33%, and 18% for
each risk group,respectively

74. • Modified Prognostic Index for T-cellLymphoma (mPIT)
• Prognostic Index for T-cell Lymphomas (PIT) + biological variable(Ki67
expression)
• mPIT distinguishes three different risk groups
• good risk prognosis, intermediate risk, and poor risk
• The International Peripheral T-cell Lymphoma Project(IPTCLP)
includes age,performance status, and platelet count

75. • CHOP regimen is the most commonly used first-line therapy for these
malignancies
• Several studies demonstrated complete response (CR)rates of 50%
and overall survival at 5 years of 30% with the CHOP regimen
• Correct identification of each entity is critical to establish appropriate
therapeutic interventions, which currently still offer poor response
rates

76. • Lymphoma classification does not rely on any single factor requires a
consideration of the clinical features, morphological appearances,
phenotypic findings, and genetic alterations

77. • Clinical Features-
• Most forms of natural killer (NK) or T cell neoplasms seen in adults,
• lymphoblastic lymphoma and ALK positive anaplastic large
• cell lymphoma (ALK+ALCL) are more common in children,
• adolescents and young adults
• Angioimmunoblastic T cell lymphoma patients commonly present
with systemic symptoms and skin rashes

78. Immunophenotype
• A T cell phenotype is typical of a T cell lymphoma but the aberrant
loss of a pan-T marker (CD2, CD3,CD5, CD7) or
• aberrant expression of a B cell marker such as CD79a or CD20 may be
rarely seen in some T cell lymphomas
• Therefore, in the diagnostic work-up of a T cell lymphoma, a wide
panel of
• immunohistochemical stains may be needed to accurately to classify a
neoplasm.

80. Take home lessons
• An excisional tumor biopsy is essential for correct diagnosis. Needle
biopsy guided by imaging is not recommended.
• It should be highlighted that for the correct diagnosis and
classification of PTCL, histopathological analysis by an experienced
hematopathologist using a large sample with a considerable amount
of tissue that allows visualization of the broad pattern of lymph node
infiltration is necessary, as well as applying a wide
immunohistochemical panel

81. • •Don’t give up on morphology
• T-cell lymphomas may not have antigenic abnormalities or a clonalTCR gene
rearrangement but beware of infectious mono and Kikuchi’s
• •Use FDC and follicular T-cell markers for AITL
• •B-cell and plasma cell proliferations may complicate PTCL and AITL
• Use light chain reagents and EBER
• •Reactive follicles do not exclude AITL

82. • WHO classification of tumours of haematopoietic and lymphoid tissues.
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83. • Lakshmanan A, Sikri D,Patil S, Kurian A, Annapurneswari S, Nair
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